Treo for BMFD Post HCT

Brief Title

Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)

Official Title

Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for the Treatment of Bone Marrow Failure Diseases

Brief Summary

      This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin
      (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to
      cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs,
      such as treosulfan, work in different ways to stop the growth of tumor cells, either by
      killing the cells, by stopping them from dividing, or by stopping them from spreading.
      Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for
      cell growth. rATG is used to decrease the body's immune response and may improve bone marrow
      function and increase blood cell counts. Adding treosulfan to a conditioning regimen with
      fludarabine and rATG may result in patients having less severe complications after a blood or
      bone marrow transplant.
    

Detailed Description

      OUTLINE:

      CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days
      -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte
      immune globulin (rATG) IV over 4-6 hours on days -4 to -2.

      TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day
      0.

      GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper
      beginning on day 180. Patients may also receive tacrolimus orally (PO). Patients also receive
      methotrexate IV on days 1, 3, 6, and 11.

      After completion of study treatment, patients are followed up at 1 year from transplant.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Graft-Versus Host-Disease (GVHD)-Free Event-Free Survival (EFS)

Secondary Outcome

 Overall Survival

Condition

Bone Marrow Failure Syndrome

Intervention

Treosulfan

Study Arms / Comparison Groups

 Treatment (conditioning regimen; transplant; GVHD prophylaxis)
Description:  CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.
TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

40

Start Date

April 19, 2022

Completion Date

December 2026

Primary Completion Date

December 2025

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must be >= 1.0 year of age and less than 50.0 years of age at the time of
             enrollment (i.e. patient must have celebrated their 1st birthday when enrolled and
             must NOT have celebrated their 50th birthday when enrolled; 49.99 years)

          -  Underlying BMFD treatable by allogenic HCT

          -  Shwachman-Diamond syndrome

               -  Criteria for Diagnosis:

                    -  A pathogenic mutation(s) for Shwachman-Diamond syndrome

                    -  For those patients tested but lacking a genetic mutation they must meet both
                       **** criteria below:

                         -  Exocrine pancreatic dysfunction as defined by at least one of the
                            following:

                              -  Pancreatic isoamylase below normal (age >= 3 years old), OR

                              -  Fecal elastase < 200, AND

                         -  Bone marrow failure as evidence by at least one of the following:

                              -  Intermittent or persistent neutropenia (absolute neutrophil count
                                 < 1,500/uL), OR

                              -  Hypo-productive anemia with a hemoglobin concentration below the
                                 age-related adjusted norms, OR

                              -  Unexplained macrocytosis, OR

                              -  Platelet count < 150,000/uL without alternative etiology, OR

                              -  Hypocellular bone marrow

               -  Indications for HCT:

                    -  Severe neutropenia (absolute neutrophil count [ANC] < 500/uL), OR

                    -  Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR

                    -  Severe thrombocytopenia (platelet count < 20,000/uL) or
                       transfusion-dependent thrombocytopenia, OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 eligibility review committee
                       (ERC). In addition, patients with severe or recurrent infections will be
                       reviewed by the ERC if they do not meet the indications for transplant
                       listed above

          -  Diamond Blackfan Anemia

               -  Criteria for Diagnosis:

                    -  A pathogenic mutation for Diamond Blackfan anemia

                    -  For those patients tested but lacking a genetic mutation the patient must
                       meet the first *** criteria and at least one of the subsequent *** criteria
                       listed below:

                         -  History of deficiency of erythroid precursors in an otherwise cellular
                            bone marrow AND,

                         -  Reticulocytopenia, OR

                         -  Elevated adenosine deaminase activity, OR

                         -  Elevated hemoglobin F, OR

                         -  Macrocytosis, OR

                         -  Congenital anomalies

               -  Indications for HCT:

                    -  Red blood cell (RBC) transfusion dependent anemia despite an adequate trial
                       of steroids; OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 ERC

          -  Congenital Sideroblastic anemia

               -  Criteria for Diagnosis:

                    -  A pathogenic mutation(s) for sideroblastic anemia

                    -  For those patients tested but lacking a genetic mutation:

                         -  Presence of ringed sideroblasts in the bone marrow excluding acquired
                            causes of ringed sideroblasts such as lead poisoning & zinc toxicity

               -  Indications for HCT:

                    -  Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 ERC

          -  GATA2 mutation with associated marrow failure

               -  Criteria for Diagnosis:

                  ** A pathogenic mutation(s) for GATA2

               -  Indications for HCT:

                    -  Severe neutropenia (ANC < 500/uL), OR

                    -  Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR

                    -  Severe thrombocytopenia (platelet count < 20,000/uL) or
                       transfusion-dependent thrombocytopenia, OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 ERC. In addition, patients
                       with severe or recurrent infections will be reviewed by the ERC if they do
                       not meet indications for transplant listed above

          -  SAMD9 or SAMD9L disorders

               -  Criteria for Diagnosis:

                  ** A pathogenic mutation(s) for SAMD9 or SAMD9L

               -  Indications for HCT:

                    -  Severe neutropenia (ANC < 500/uL), OR

                    -  Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR

                    -  Severe thrombocytopenia (platelet count < 20,000/uL) or
                       transfusion-dependent thrombocytopenia, OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 ERC

          -  Congenital amegakaryocytic thrombocytopenia

               -  Criteria for Diagnosis:

                    -  A pathogenic mutation(s) for congenital amegakaryocytic thrombocytopenia.

                    -  For those patients tested but lacking a genetic mutation the patient must
                       meet criteria below:

                         -  Thrombocytopenia early in life, AND

                         -  History of bone marrow demonstrating megakaryocyte hypoplasia

               -  Indications for HCT:

                    -  Severe thrombocytopenia (platelet count < 20,000/uL) or
                       transfusion-dependent thrombocytopenia, OR

                    -  Neutropenia defined as an ANC < 500/uL, OR

                    -  Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 ERC

          -  Paroxysmal nocturnal hemoglobinuria

               -  Criteria for Diagnosis:

                    -  Paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes >= 10%,
                       AND

                    -  Complement mediated intravascular hemolysis with an elevated LDH (above
                       institutional upper limits of normal)

               -  Indications for HCT:

                    -  PNH with thrombosis despite adequate medical management, OR

                    -  PNH with intravascular hemolysis requiring transfusion support despite
                       adequate medical management, OR

                    -  Additional clinical or laboratory data may be considered for protocol
                       eligibility following review by protocol 1904 ERC. In addition, patients
                       with PNH and cytopenias may be considered for the protocol eligibility
                       following review by protocol 1904 ERC

          -  An undefined BMFD: a patient with a BMFD for whom a genetic mutation responsible for
             their bone marrow failure phenotype has not been identified (excluding PNH) will be
             eligible for this clinical trial following approval by Blood and Marrow Transplant
             Clinical Trials Network (BMT CTN) 1904 ERC

             * A BMFD with a known genetic mutation but not listed above will be eligible for this
             clinical trial following approval by BMT CTN 1904 ERC

          -  Patient and/or legal guardian must sign informed consent prior to initiation of
             conditioning for BMT CTN 1904

          -  Females and males of childbearing potential must agree to practice 2 effective methods
             of contraception at the same time or agree to abstinence

          -  Note: The following patients MUST be reviewed by the BMT CTN 1904 ERC in order to
             determine if they are eligible for this trial:

               -  All patients with Shwachman-Diamond syndrome, Diamond Blackfan anemia, congenital
                  sideroblastic anemia, and congenital amegakaryocytic thrombocytopenia who have
                  had genetic testing and lack a genetic mutation

               -  All patients with an undefined BMFD: a patient with a BMFD for whom a genetic
                  mutation responsible for their bone marrow failure phenotype has not been
                  identified, excluding PNH

               -  All patients with a BMFD and a known genetic mutation that is not listed above

               -  All patients with GATA2 mutation and associated marrow failure

               -  All patients with SAMD9 or SAMD9L disorders

               -  There may be circumstances where a treating physician will consider a transplant
                  for a patient with a BMFD who does not meet all the criteria listed under
                  "indications for HCT". In these situations, treating physicians may submit their
                  patient to the BMT CTN 1904 ERC for review in order to determine if the patient
                  is eligible for this clinical trial based on additional clinical or laboratory
                  information

               -  Many patients with BMFD can have bone marrow evaluations that raise concern for
                  possible myelodysplastic syndrome (MDS) including but not limited to dysplastic
                  bone marrow evaluations or cytogenetic abnormalities. However, in patients BMFD
                  these findings are not necessarily diagnostic or consistent with MDS. Therefore,
                  given the complexities of diagnosing MDS in patients with BMFD, all patients with
                  bone marrow evaluations concerning for possible MDS should be submitted to the
                  ERC for review to confirm or exclude MDS. This is particularly important as we do
                  not want to exclude potentially eligible patients due to an incorrect diagnosis
                  of MDS

          -  HLA-MATCHED RELATED DONOR: HLA-matched sibling: Must be a minimum HLA-6/6 matched to
             the recipient at HLA-A, -B (serologic typing) and DRB1 (high-resolution typing)

          -  HLA-MATCHED RELATED DONOR: HLA-matched related (phenotypic match): Fully matched for
             HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing.

          -  HLA-MATCHED RELATED DONOR: If a genetic mutation is known for the patient, the
             HLA-matched related donor [either HLA-matched sibling or HLA-matched related
             (phenotypic match)] must be screened for the same genetic mutation if clinically
             appropriate and should be confirmed to not have the same genetic disease (this does
             not include patients with PNH). Consult the protocol team with questions

          -  HLA-MATCHED RELATED DONOR: If a patient has an undefined BMFD (a patient with a BMFD
             for whom a genetic mutation responsible for their bone marrow failure phenotype has
             not been identified), the HLA-matched related donor [either HLA-matched sibling or
             HLA-matched related (phenotypic match)] must have an evaluation as directed by the
             treating physician to confirm that the donor does not have the same underlying
             disease. This will include a complete blood count (CBC) with differential and
             potentially a bone marrow evaluation or other studies as directed by the treating
             physician

          -  UNRELATED DONOR: Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution
             typing

          -  UNRELATED DONOR: Mismatched for a single HLA-class 1 allele (HLA-A, -B, or -C) by
             high-resolution typing; OR

          -  UNRELATED DONOR: Mismatched for a single HLA DQB1 allele or antigen by high-resolution
             typing

             * Note: donor patient (DP) matching per institutional practice

          -  DONOR SELECTION RECCOMENDATIONS: in the case where there are multiple donor options,
             donors should be selected based on the following priority numbered below:

               -  Unaffected fully HLA-matched sibling

               -  Unaffected fully phenotypically HLA-matched related donor

               -  Fully HLA-matched unrelated donor

               -  Unrelated donor with single allele or antigen level mismatch at DQB1

               -  Unrelated donor with single allele level mismatch at class 1 (HLA-A, -B, or -C)

        Exclusion Criteria:

          -  Patients with idiopathic aplastic anemia, Fanconi anemia, dyskeratosis congenita, and
             congenital neutropenia

          -  Patients with MDS as defined by the World Health Organization (WHO) or leukemia

          -  Prior allogeneic HCT

          -  Patient's weight =< 10.0 kg (actual body weight and adjusted body weight) at time of
             study enrollment

          -  Lansky (patients < 16 years of age) or Karnofsky (patients >= 16 years of age)
             performance < 70%

          -  Left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition
             (MUGA) scan

             * For patients unable to obtain a left ventricular ejection fraction, left ventricular
             shortening fraction of < 26%

          -  Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected/adjusted for
             hemoglobin) < 50%, forced expiratory volume (FEV)1 < 50% predicted, and forced vital
             capacity (FVC) < 50% predicted

          -  For patients unable to perform pulmonary function tests (PFTs) due to age or
             developmental delay: oxygen (O2) saturation < 92% on room air

          -  On supplemental oxygen

          -  Estimated creatinine clearance < 60 mL/minute/1.73m^2 (estimated per institutional
             practice)

          -  Dialysis dependent

          -  Conjugated bilirubin > 2 x ULN for age (upper limit of normal [ULN], unless
             attributable to Gilbert's syndrome)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 4 x ULN for age,
             or

          -  Fulminant liver failure or cirrhosis

          -  Iron overload - This exclusion criterion only applies to patients who are considered
             at risk for hepatic or cardiac iron overload. Therefore, not all patients enrolled on
             this protocol will undergo formal hepatic or cardiac iron assessment

               -  For patients >= 18 years with a history of significant transfusions defined as >=
                  8 packed red blood cell transfusions per year for >= 1 year or have received >=
                  20 packed red blood cell transfusions (lifetime cumulative) will require formal
                  hepatic and cardiac iron measurement. In addition, patients with a prior history
                  of hepatic or cardiac iron overload will also require formal assessment for iron
                  overload. Patients are excluded if:

                    -  Hepatic iron content >= 8 mg Fe/g dry weight by liver magnetic resonance
                       imaging (MRI) using a validated methodology (such as T2 * MRI or ferriscan)
                       or liver biopsy per institutional practice

                    -  Cardiac iron content < 25 msec by cardiac T2 * MRI

               -  For patients < 18 years old with a history of significant transfusions defined as
                  >= 8 packed red blood cell transfusions per year for >= 1 year or have received
                  >= 20 packed red blood cell transfusions (lifetime cumulative) will require
                  formal hepatic iron measurement. In addition, patients with a prior history of
                  liver iron overload will also require formal assessment for iron overload.
                  Patients are excluded if:

                    -  Hepatic iron content >= 8 mg Fe/g dry weight by liver MRI using a validated
                       methodology (such as T2 * MRI or ferriscan) or liver biopsy per
                       institutional practice

          -  Uncontrolled bacterial infection within 1 week of study enrollment. Uncontrolled is
             defined as currently taking medication with no clinical improvement or progression on
             adequate medical treatment

          -  Uncontrolled viral or fungal infection within 30 days of study enrollment.
             Uncontrolled is defined as currently taking medication with no clinical improvement or
             progression on adequate medical treatment

          -  Positive for human immunodeficiency virus (HIV)

          -  Presence of clinically significant anti-donor human leukocyte antigen (HLA)-antibodies
             per institutional practice

          -  Prior solid organ transplant

          -  Patients with prior malignancies except resected non-melanoma skin cancer or treated
             cervical carcinoma in situ

          -  Demonstrated lack of compliance with prior medical care as determined by referring
             physician

          -  Females who are pregnant or breast-feeding

          -  Known hypersensitivity to treosulfan or fludarabine

          -  Known life-threatening reaction (i.e. anaphylaxis) to Thymoglobulin that would
             prohibit use for the patient as this study requires use of the Thymoglobulin
             preparation of anti-thymocyte globulin (ATG)
      

Gender

All

Ages

1 Year - 49 Years

Accepts Healthy Volunteers

No

Contacts

Lauri Burroughs, MD, 240-599-5648, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04965597

Organization ID

BMTCTN1904

Secondary IDs

2U10HL069294-11

Responsible Party

Sponsor

Study Sponsor

Fred Hutchinson Cancer Center

Collaborators

 Blood and Marrow Transplant Clinical Trials Network

Study Sponsor

Lauri Burroughs, MD, Study Chair, Fred Hutch/University of Washington Cancer Consortium


Verification Date

February 2022