Treo for BMFD Post HCT

Brief Title

HCT Using Treosulfan for Bone Marrow Failure Diseases

Official Title

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

Brief Summary

      This is a prospective, multicenter phase II study designed to evaluate the outcomes of
      patients with bone marrow failure diseases (BMFD) undergoing HLA-matched related, HLA-matched
      unrelated, or single HLA-class 1 allele or HLA-DQB1 antigen or allele mismatched unrelated
      hematopoietic cell transplantation (HCT) using treosulfan-based conditioning.
    

Detailed Description

      Patients will be treated with a preparative regimen of treosulfan (total dose 30-42 g/m2),
      fludarabine (total dose 150 mg/m2), and Thymoglobulin (total dose 6 mg/kg). GVHD prophylaxis
      will be with tacrolimus and methotrexate.

      Patients will be followed for 1-year post-HCT.
    

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 Disorders

Intervention

Treosulfan

Study Arms / Comparison Groups

 treosulfan, fludarabine and Thymoglobulin, tacrolimus and methotrexate
Description:  Patients will be treated with a preparative regimen of treosulfan (total dose 30-42 g/m2), fludarabine (total dose 150 mg/m2), and Thymoglobulin (total dose 6 mg/kg). GVHD prophylaxis will be with tacrolimus and methotrexate.

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

August 2021

Completion Date

December 2026

Primary Completion Date

December 2025

Eligibility Criteria

        Inclusion Criteria:

          -  1. 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).

             2. Underlying bone marrow failure disorders treatable by allogenic HCT.

             a. Shwachman-Diamond syndrome i. Criteria for Diagnosis:

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

               2. For those patients tested but lacking a genetic mutation they must meet both
                  criteria a and b below:

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

                  i. Pancreatic isoamylase below normal (age >3 years old), OR ii. Fecal elastase
                  <200, AND b. Bone marrow failure as evidenced by at least one of the following:
                  i. Intermittent or persistent neutropenia (absolute neutrophil count < 1,500/μL),
                  OR ii. Hypo-productive anemia with a hemoglobin concentration below the
                  age-related adjusted norms, OR iii. Unexplained macrocytosis, OR iv. Platelet
                  count <150,000/μL without alternative etiology, OR v. Hypocellular bone marrow

                  ii. Indications for HCT:

             1. Severe neutropenia (ANC <500/μL), OR 2. Severe anemia (hemoglobin <8 g/dL) or
             transfusion-dependent anemia, OR 3. Severe thrombocytopenia (platelet count
             <20,000/μL) or transfusion-dependent thrombocytopenia, OR 4. 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 indications for
             transplant listed above.

             b. Diamond Blackfan anemia i. Criteria for Diagnosis:

               1. A pathogenic mutation for Diamond Blackfan anemia

               2. For those patients tested but lacking a genetic mutation the patient must meet
                  criteria a and at least one of the criteria listed in b-f:

                  a. History of deficiency of erythroid precursors in an otherwise cellular bone
                  marrow AND, b. Reticulocytopenia, OR c. Elevated adenosine deaminase activity, OR
                  d. Elevated hemoglobin F, OR e. Macrocytosis, OR f. Congenital anomalies ii.
                  Indications for HCT:

             1. RBC transfusion dependent anemia despite an adequate trial of steroids; OR 2.
             Additional clinical or laboratory data may be considered for protocol eligibility
             following review by protocol 1904 ERC.

             c. Congenital Sideroblastic anemia i. Criteria for Diagnosis:

               1. A pathogenic mutation(s) for sideroblastic anemia

               2. For those patients tested but lacking a genetic mutation:

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

                  ii. Indications for HCT:

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

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

                  d. GATA2 mutation with associated marrow failure i. Criteria for Diagnosis:

               1. A pathogenic mutation(s) for GATA2

                  ii. Indications for HCT:

               1. Severe neutropenia (ANC <500/μL), OR

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

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

               4. 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 the
                  indications for transplant listed above.

                  e. SAMD9 or SAMD9L disorders i. Criteria for Diagnosis:

               1. A pathogenic mutation(s) for SAMD9 or SAMD9L

                  ii. Indications for HCT:

             1. Severe neutropenia (ANC <500/μL), OR 2. Severe anemia (hemoglobin <8 g/dL) or
             transfusion-dependent anemia, OR 3. Severe thrombocytopenia (platelet count
             <20,000/μL) or transfusion-dependent thrombocytopenia, OR 4. Additional clinical or
             laboratory data may be considered for protocol eligibility following review by
             protocol 1904 ERC.

             f. Congenital amegakaryocytic thrombocytopenia i. Criteria for Diagnosis:

             1. A pathogenic mutation(s) for congenital amegakaryocytic thrombocytopenia. 2. For
             those patients tested but lacking a genetic mutation the patient must meet criteria a
             and b below:

               1. Thrombocytopenia early in life, AND

               2. History of bone marrow demonstrating megakaryocyte hypoplasia.

                  ii. Indications for HCT:

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

                    2. Neutropenia defined as an ANC <500/μL, OR

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

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

             g. Paroxysmal nocturnal hemoglobinuria (PNH) i. Criteria for Diagnosis:

               1. PNH clone size in granulocytes > 10%, AND

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

                  ii. Indications for HCT:

               1. PNH with thrombosis despite adequate medical management, OR

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

               3. 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.

                  h. 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
                  BMT CTN 1904 ERC.

                  i. 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.

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

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

                  b. 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.

                  c. All patients with a BMFD and a known genetic mutation that is not listed above
                  d. All patients with GATA2 mutation with associated marrow failure e. All
                  patients with SAMD9 or SAMD9L disorders f. 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.

                  g. 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 with 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 expert 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.

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

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

        Exclusion Criteria:

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

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

             3. Prior allogeneic transplant 4. Patient's weight ≤10.0 kg at time of study
             enrollment 5. Lansky (patients < 16 years of age) or Karnofsky (patients ≥16 years of
             age) performance <70% 6. Organ Dysfunction defined as follows:

             a. Cardiac: i. Left ventricular ejection fraction <50% by echocardiogram or
             multi-gated acquisition (MUGA) scan.

        ii. For patients unable to obtain a left ventricular ejection fraction, left ventricular
        shortening fraction <26%.

        b. Pulmonary: i. DLCO (corrected/adjusted for hemoglobin), FEV1, and FVC <50% predicted.
        ii. For patients unable to perform pulmonary function tests (PFTs) due to age or
        developmental delay: Oxygen saturation <92% on room air.

        iii. On supplemental oxygen. c. Renal: i. Estimated creatinine clearance <60
        mL/minute/1.73m2 (estimated per institutional practice).

        ii. Dialysis dependent d. Hepatic: i. Conjugated bilirubin > 2x upper limit of normal for
        age (ULN, unless attributable to Gilbert's syndrome), or ii. AST or ALT > 4x ULN for age,
        or iii. Fulminant liver failure or cirrhosis 7. 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.

          1. 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:

        i. 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.

        ii. Cardiac iron content < 25 msec by cardiac T2* MRI. b. 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 hepatic iron overload will also require formal assessment for iron
        overload. Patients are excluded if: i. 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.

        8. 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.

        9. 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.

        10. Positive for HIV (human immunodeficiency virus). 11. Presence of clinically significant
        anti-donor HLA-antibodies per institutional practice.

        12. Prior solid organ transplant. 13. Patients with prior malignancies except resected
        non-melanoma skin cancer or treated cervical carcinoma in situ.

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

        15. Females who are pregnant or breast-feeding. 16. 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 - 50 Years

Accepts Healthy Volunteers

No

Contacts

Lauri Burroughs, M.D., 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 Research Center

Collaborators

 Blood and Marrow Transplant Clinical Trials Network

Study Sponsor

Lauri Burroughs, M.D., Study Chair, Fred Hutch/University of Washington Cancer Consortium


Verification Date

July 2021