Clinical Trials /

Total Marrow and Lymphoid Irradiation, Fludarabine, and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome

NCT03494569

Description:

This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor stem cell transplant in treating participants with high-risk acute leukemia or myelodysplastic syndrome. Giving chemotherapy, such as fludarabine and melphalan, and total marrow and lymphoid irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Secondary Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Total Marrow and Lymphoid Irradiation, Fludarabine, and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome
  • Official Title: Phase I Study of Escalating Doses of Total Marrow and Lymphoid Irradiation (TMLI) Combined With Fludarabine and Melphalan as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With High-Risk Acute Leukemia or Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: 17505
  • SECONDARY ID: NCI-2018-00497
  • SECONDARY ID: 17505
  • NCT ID: NCT03494569

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Lymphoblastic Leukemia in Remission
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia in Remission
  • Hematopoietic Cell Transplantation Recipient
  • Minimal Residual Disease
  • Myelodysplastic Syndrome
  • Secondary Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
FludarabineFluradosaTreatment (TMLI, fludarabine, melphalan)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (TMLI, fludarabine, melphalan)

Purpose

This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor stem cell transplant in treating participants with high-risk acute leukemia or myelodysplastic syndrome. Giving chemotherapy, such as fludarabine and melphalan, and total marrow and lymphoid irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of total
      marrow and lymphoid irradiation (TMLI) with fixed doses of fludarabine and melphalan (FM100)
      as a preparative regimen in patients undergoing allogeneic hematopoietic stem cell
      transplantation (alloHCT) and who are not eligible for standard myeloablative regimens, with
      either a matched donor (Arm A) or a haploidentical donor (Arm B).

      II. To describe toxicities attributable to TMLI by dose level in patients treated under this
      regimen.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety of the regimen, at each dose level, by assessing the following:
      type, frequency, severity, attribution, time course and duration of adverse events, including
      acute/chronic graft versus host disease (GVHD), infection and delayed engraftment.

      II. To investigate the temporal effect of bone marrow residual damage in alloHCT patients
      after TMLI/FM100.

      III. To estimate overall survival (OS), event-free survival (EFS), cumulative incidence (CI)
      of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

      IV. Assess minimal residual disease (MRD) from bone marrow aspirates on days 30, 100, and 180
      post-transplant and describe its relation to TMLI dose level and patient disease status.

      V. To evaluate effect of TMLI/FM100 conditioning on immune reconstitution after alloHCT in
      patients receiving stem cells from matched or haploidentical donors.

      OUTLINE: This is a dose-escalation study of TMLI.

      Participants undergo TMLI twice daily (BID) on days -8 to -5, and receive fludarabine
      intravenously (IV) on days -4 to -2 and melphalan on day -2. Participants then undergo
      alloHCT on day 0.

      After completion of study treatment, participants are followed up twice weekly for 100 days,
      twice monthly for 6 months, and then monthly or yearly for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (TMLI, fludarabine, melphalan)ExperimentalParticipants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
  • Fludarabine
  • Melphalan

Eligibility Criteria

        Inclusion Criteria:

          -  Eligible patients with a histopathological confirmed diagnosis of hematologic
             malignancy in one of the following categories:

               -  Acute myelogenous leukemia:

                    -  Patients with de novo or secondary disease in unfavorable risk group
                       including poor risk cytogenetics according to National Comprehensive Cancer
                       Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5, 5q-, -7,
                       7q-, 11q23-non t (9;11), inv (3), t (3;3),t (6;9), t (9;22) and complex
                       karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate
                       risk groups accept patients with FLT3-NPM1+ disease

                    -  Patients with active disease

                    -  Patients with chemosensitive active disease

               -  Acute lymphocytic leukemia:

                    -  Patients with de novo or secondary disease according to NCCN guidelines for
                       ALL hypoploidy (< 44 chromosomes); t (v;11q23): MLL rearranged; t (9;22)
                       (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities);
                       high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000
                       for T lineage); iAMP21loss of 13q, and abnormal 17p

                    -  Patients with active disease

                    -  Patients with chemosensitive active disease

               -  Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories

          -  Patients ≥ 12 years and < 55 years are also included if they are not candidates for
             myeloablative conditioning regimens due to comorbidities

          -  Karnofsky or Lansky performance status of ≥ 70

          -  A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute

          -  Patients must have a serum bilirubin ≤ 2.0 mg/dl

          -  Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase
             (SGPT) ≤ 2.5 times the institutional upper limits of normal

          -  Ejection fraction measured by echocardiogram or multigated acquisition (MUGA) ≥ 50%

          -  Carbon monoxide diffusing capacity (DLCO) and forced expiratory volume FEV1 > 50%
             predicted

          -  PATIENT-SPECIFIC INCLUSION CRITERIA

          -  Patients should have discontinued all previous intensive therapy, chemotherapy or
             radiotherapy for 2 weeks prior to commencing therapy on this study

               -  NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of
                  planned study enrollment is permitted; these include hydroxyurea,
                  6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine
                  kinase inhibitors (TKIs); FLT-3 inhibitors can also be given up to 3 days before
                  conditioning regimen

               -  All patients with prior radiation treatment to the lung, liver, and kidney will
                  be excluded; for other scenarios of prior radiation treatment, up to 2000 cGY at
                  2 gray Gy per day will be allowed; inclusion of patients with previous radiation
                  exposure will be determined based on the radiation oncologist MD evaluation and
                  judgment

          -  DONOR: Arm A: All candidates for this study must have an human leukocyte antigen (HLA)
             (A, B, C, and DR) identical sibling who is willing to donate primed blood stem cells
             (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched
             unrelated donor; DQ or DP mismatch is allowed per discretion of the principal
             investigator

          -  DONOR: Arm B: The recipient must have a related donor genotypically HLA-A, B, C and
             DRB1 loci haploidentical to the recipient; no HLA matched sibling or matched unrelated
             donor is available; DSA is allowed with desensitization done if recommended by donor
             selection committee (DSC) per City of Hope (COH) standard operating procedures (SOP)

          -  DONOR: Both arms: All donors in both arms should be evaluated and approved by DSC

        Exclusion Criteria:

          -  Having any uncontrolled illness including ongoing or active bacterial, viral or fungal
             infection

          -  Receiving any investigational agents or concurrent biological, intensive chemotherapy
             or radiation therapy for the previous 2 weeks from conditioning

               -  NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of
                  planned study enrollment is permitted; these include: hydroxyurea,
                  6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine
                  kinase inhibitors (TKIs), FLT-3 inhibitors can also be given up to 3 days before
                  conditioning regimen

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to any in the regimen

          -  Patients with other malignancies are ineligible for this study, other than
             non-melanoma skin cancers

          -  The recipient has another medical problem or neurologic/psychiatric dysfunction which
             would impair his/her ability to be compliant with the medical regimen and to tolerate
             transplantation or would prolong hematologic recovery in which the opinion of the
             principal investigator would place the recipient at unacceptable risk

          -  Patients may not have had a prior autologous or allogeneic transplant

          -  Patients may not have received more than 3 prior lines of intensive chemotherapy,
             where the regimen intent was to induce remission

          -  In the opinion of the principal investigator (PI), the participant has a condition
             that will preclude them from complying with study treatment

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control or abstinence) prior to study entry and
             for six months following duration of study participation; should a woman become
             pregnant or suspect that she is pregnant while participating on the trial, she should
             inform her treating physician immediately

          -  All subjects must have the ability to understand and the willingness to sign a written
             informed consent; they are to give voluntary written informed consent before
             performance if any study-related procedure not part of normal medical care, with the
             understanding that consent may be withdrawn by the subject at any time without
             prejudice to future medical care; cognitively impaired subjects will be included only
             if their guardian or legal representative agrees to sign the written informed consent

          -  DONOR: Donor selection for both arms must be approved by the donor selection committee

          -  DONOR: Evidence of active infection

          -  DONOR: Medical or physical reason which makes the donor unlikely to tolerate or
             cooperate with growth factor therapy or leukapheresis

          -  DONOR: Factors which place the donor at increased risk for complications from
             leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy could be
             harvested for bone marrow (BM) if safer for the donor and if approved by the principal
             investigator (PI)

          -  DONOR: Human immunodeficiency virus (HIV) positive
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity
Time Frame:Up to 2 years
Safety Issue:
Description:Toxicity will be scored on both the Bearman scale and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5 scale. Toxicity information recorded in each patient will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity, and dose levels in each arm.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From start of protocol therapy up to 2 years
Safety Issue:
Description:Participants are considered a failure for this endpoint if they die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.
Measure:Event-free survival
Time Frame:From start of protocol therapy up to 2 years
Safety Issue:
Description:Participants are considered a failure for this endpoint if they relapse/progress or die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.
Measure:Relapse/progression
Time Frame:From start of protocol therapy up to 2 years
Safety Issue:
Description:Death without relapse/progression is considered a competing risk.
Measure:Complete remission proportion
Time Frame:At day 30
Safety Issue:
Description:
Measure:Non-relapse mortality
Time Frame:Up to 2 years
Safety Issue:
Description:Participants are considered a failure for this endpoint if they die from causes other than disease relapse or progression.
Measure:Incidence of infection
Time Frame:Up to day 100 post-transplant
Safety Issue:
Description:Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. These data will be captured via case report form.
Measure:Incidence of toxicities/adverse events (AEs)
Time Frame:Up to 100 days post-transplant
Safety Issue:
Description:Toxicities that meet grade 3, 4, or 5 per the Bearman scale and CTCAE v 4.03 from day -9 to day -1, from day 0 to day +30, and again from day +31 to +100 post-transplant will be collected. Any AEs occurring from day -9 to day +30 will be followed until they resolve. Start and stop dates will also be recorded for any grade 4 neutropenia.
Measure:Neutrophil recovery
Time Frame:Up to 2 years
Safety Issue:
Description:This will be measured from stem cell infusion to the first to three consecutive days with neutrophil count greater than 0.5 x 10^9/l.
Measure:Acute graft versus host disease of grades 2-4 and 3-4
Time Frame:Up to 100 days post-transplant
Safety Issue:
Description:Documented/biopsy proven acute graft versus host disease is graded according to National Institutes of Health (NIH) consensus staging. This measurement will be used to estimate the cumulative incidence.
Measure:Chronic graft versus host disease
Time Frame:Up to 2 years
Safety Issue:
Description:This will be scored according to NIH consensus staging and will be used to estimate the cumulative incidence.
Measure:CD4+, CD8+ and CD56+16+
Time Frame:Up to 2 years
Safety Issue:
Description:Immunophenotyping of lymphocyte subsets will be determined by flow cytometry.
Measure:Bone marrow (BM) residual damage
Time Frame:Up to 2 years
Safety Issue:
Description:BM cellularity will be assessed using histology and clonogenic in vitro assays.
Measure:Immune reconstitution
Time Frame:Up to 2 years
Safety Issue:
Description:This will be monitored by flow cytometry analysis of peripheral blood mononuclear cells.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

November 18, 2019