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

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ClinicalTrials.gov Identifier: NCT03494569
Recruitment Status : Recruiting
First Posted : April 11, 2018
Last Update Posted : November 19, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE April 4, 2018
First Posted Date  ICMJE April 11, 2018
Last Update Posted Date November 19, 2019
Actual Study Start Date  ICMJE July 6, 2018
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 4, 2018)
Incidence of toxicity [ Time Frame: Up to 2 years ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 4, 2018)
  • Overall survival [ Time Frame: From start of protocol therapy up to 2 years ]
    Participants are considered a failure for this endpoint if they die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.
  • Event-free survival [ Time Frame: From start of protocol therapy up to 2 years ]
    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.
  • Relapse/progression [ Time Frame: From start of protocol therapy up to 2 years ]
    Death without relapse/progression is considered a competing risk.
  • Complete remission proportion [ Time Frame: At day 30 ]
  • Non-relapse mortality [ Time Frame: Up to 2 years ]
    Participants are considered a failure for this endpoint if they die from causes other than disease relapse or progression.
  • Incidence of infection [ Time Frame: Up to day 100 post-transplant ]
    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.
  • Incidence of toxicities/adverse events (AEs) [ Time Frame: Up to 100 days post-transplant ]
    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.
  • Neutrophil recovery [ Time Frame: Up to 2 years ]
    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.
  • Acute graft versus host disease of grades 2-4 and 3-4 [ Time Frame: Up to 100 days post-transplant ]
    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.
  • Chronic graft versus host disease [ Time Frame: Up to 2 years ]
    This will be scored according to NIH consensus staging and will be used to estimate the cumulative incidence.
  • CD4+, CD8+ and CD56+16+ [ Time Frame: Up to 2 years ]
    Immunophenotyping of lymphocyte subsets will be determined by flow cytometry.
  • Bone marrow (BM) residual damage [ Time Frame: Up to 2 years ]
    BM cellularity will be assessed using histology and clonogenic in vitro assays.
  • Immune reconstitution [ Time Frame: Up to 2 years ]
    This will be monitored by flow cytometry analysis of peripheral blood mononuclear cells.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Fludarabine
    Given IV
    Other Name: Fluradosa
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Melphalan
    Given as per City of Hope Standard Operating Procedure
    Other Names:
    • Alanine 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-19813
  • Radiation: Total Marrow Irradiation
    Undergo TMLI
Study Arms  ICMJE Experimental: Treatment (TMLI, fludarabine, melphalan)
Participants 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.
Interventions:
  • Drug: Fludarabine
  • Other: Laboratory Biomarker Analysis
  • Drug: Melphalan
  • Radiation: Total Marrow Irradiation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 4, 2018)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03494569
Other Study ID Numbers  ICMJE 17505
NCI-2018-00497 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17505 ( Other Identifier: City of Hope Medical Center )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Monzr Al Malki City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP