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Total Marrow and Lymphoid Irradiation Before Donor Transplant and Cyclophosphamide in Treating Patients With Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03467386
Recruitment Status : Recruiting
First Posted : March 16, 2018
Last Update Posted : November 1, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This pilot phase I trial studies the side effects of total bone marrow and lymphoid irradiation and how well it works with cyclophosphamide in treating patients with acute myeloid leukemia. Total marrow and lymphoid irradiation targets cancer in bone marrow and blood, instead of applying radiation to the whole body. Giving total bone marrow and lymphoid irradiation before a donor transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving total bone marrow and lymphoid irradiation before donor transplant and cyclophosphamide after transplant may work better at treating acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Hematopoietic Cell Transplant Recipient Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Biological: Filgrastim Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Tacrolimus Radiation: Total Marrow Irradiation Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the safety/feasibility of combining a total marrow and lymphoid irradiation (TMLI) transplant conditioning regimen with a post-transplant high dose cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis strategy, through the assessment of: adverse events: type, frequency, severity, attribution, time course, duration and complications: including acute GvHD, infection and delayed neutrophil/platelet engraftment.

SECONDARY OBJECTIVES:

I. To estimate the cumulative incidence (CI) of acute GvHD at 100 days post allogeneic hematopoietic cell transplantation (alloHCT).

II. To estimate the CI of chronic GvHD at 6 months, 1- and 2-years post alloHCT.

III. To estimate GVHD-free relapse-free survival (GRFS) at 1- and 2-years post alloHCT.

IV. To describe the kinetics of immune reconstitution and T cell repertoire in the first year post alloHCT.

V. To estimate overall survival (OS), relapse-free survival (RFS) and CI of relapse, and non-relapse mortality (NRM) at 100 days, 1- and 2-years post alloHCT.

VI. To characterize quality of life using 36-Item Short Form Health Survey (SF-36), Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and M. D. Anderson Symptom Inventory (MDASI) or Pediatric Quality of Life Inventory (PedsQL) at 100 days, 6 months, 1- and 2-years post alloHCT.

VII. To assess bone marrow cellularity from bone marrow samples. VIII. To assess the clonogenic potential of cells from bone marrow samples. IX. To assess stromal damage from bone marrow samples. X. To evaluate cytokines and oxidative stress markers.

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

Patients undergo TMLI twice daily (BID) on days -4 to 0, then undergo bone marrow or peripheral blood stem cell transplant on day 0. Patients receive cyclophosphamide intravenously (IV) over 2 hours on days 3 and 4, tacrolimus given by continuous intravenous infusion (CIV) on days 5-90, and filgrastim beginning on day 5 until absolute neutrophil count (ANC) 1,500/mm^3 for 3 consecutive days.

After completion of study treatment, patients are followed for up to 24 months.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Total Marrow/Lymphoid Irradiation (TMLI) Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplant (HCT) Followed by Post Transplant Cyclophosphamide-Based Graft Versus Host Disease Prophylaxis for Acute Myelogenous Leukemia in Complete Remission
Actual Study Start Date : March 19, 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: Treatment (TMLI, cyclophosphamide)
Patients undergo TMLI BID on days -4 to 0, then undergo bone marrow or peripheral blood stem cell transplant on day 0. Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus given by CIV on days 5-90, and filgrastim beginning on day 5 until ANC is at least 1,500/mm^3 for 3 consecutive days.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
undergo alloHCT
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Biological: Filgrastim
Administer according to City of Hope standard operating procedures
Other Names:
  • FILGRASTIM, LICENSE HOLDER UNSPECIFIED
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Tacrolimus
Given CIV
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic

Radiation: Total Marrow Irradiation
Undergo TMLI




Primary Outcome Measures :
  1. 1a. Incidence of adverse events [ Time Frame: Up to 24 months ]
    Assessed using Bearman Scale Regimen-Related Toxicity scale. Scale range: Grade 0-4 (increasing grade reflects increasing severity), where Grade 0-none/did not experience and Grade 4=death.

  2. 1b. Incidence of adverse events [ Time Frame: Up to 24 months ]
    Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scale.Scale range: Grade 1-5 (increasing grade reflects increasing severity), where Grade 1 reflects a more milder form of the adverse event and Grade 5=death.


Secondary Outcome Measures :
  1. Acute graft versus host disease (GvHD) [ Time Frame: Day 0 to 100 (120) days post-transplant ]
    Graded according to the Consensus Grading. The first day of acute GvHD onset at a certain grade will be used to calculate cumulative incidence curves for that GvHD grade; relapse/death prior to onset will be considered competing events. Will be calculated using the competing risk method as described by Gooley et al. (1999).

  2. Bone marrow residual damage assessment [ Time Frame: Up to 24 months ]
  3. Chronic GVHD [ Time Frame: From day (80) 100 to the onset of chronic GvHD, death or last contact, whichever comes first, assessed up to 24 months ]
    The first day of chronic GvHD onset will be used to calculate cumulative incidence curves, with relapse/death prior to onset considered competing events. Will be calculated using the competing risk method as described by Gooley et al. (1999).

  4. Cytokines [ Time Frame: Up to 24 months ]
  5. GvHD-free/relapse-free survival (GRFS) [ Time Frame: From start of treatment (hematopoietic stem cell transplant [HCT]) to grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurs first, assessed up to 24 months ]
    Will be calculated using the Kaplan-Meier method.

  6. Levels of immune cells [ Time Frame: Up to 24 months ]
    Will be measured by flow cytometry for cell subsets: a. T-cells

  7. Levels of immune cells [ Time Frame: Up to 24 months ]
    Will be measured by flow cytometry for cell subsets: b. B-cells.

  8. Levels of immune cells [ Time Frame: Up to 24 months ]
    Will be measured by flow cytometry for cell subsets: c. natural killer (NK) cells.

  9. Levels of immune cells [ Time Frame: Up to 24 months ]
    Will be measured by flow cytometry for cell subsets: d. regulatory T cells (T-regs).

  10. Non-relapse mortality (NRM) [ Time Frame: From start of treatment until non-disease related death, or last follow-up, whichever comes first, assessed up to 24 months ]
    The cumulative incidence of NRM will be calculated reflecting relapse as a competing risk. Will be calculated using the Kaplan-Meier method and the competing risk method as described by Gooley et al. (1999).

  11. Overall survival [ Time Frame: From start of treatment until death, or last follow-up, whichever comes first, assessed up to 24 months ]
    Will be calculated using the Kaplan-Meier method.

  12. Oxidative stress [ Time Frame: Up to 24 months ]
  13. 15a. Quality of life [ Time Frame: Up to 24 months ]

    assessed using 36-Item Short Form Health Survey (SF-36). The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

    The eight sections are:

    • 15a1. vitality
    • 15a2. physical functioning
    • 15a3. bodily pain
    • 15a4. general health perceptions
    • 15a5. physical role functioning
    • 15a6. emotional role functioning
    • 15a7. social role functioning
    • 15a8. mental health

  14. 15b. Quality of life [ Time Frame: Up to 24 months ]

    Assessed using b. Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). (FACT-BMT) is a 47-item, valid and reliable measure of five dimensions of quality of life in bone marrow transplant patients. The dimensions collected and assessed are:

    • 15b1.physical well being
    • 15b2. Social and family well being
    • 15b3. Emotional well being
    • 15b4. Functional well being
    • 15b5. Additional concerns.

  15. 15c. Quality of life Assessed using c. M. D. Anderson Symptom Inventory (MDASI). [ Time Frame: Up to 24 months ]

    (MDASI) is a multi-symptom patient-reported outcome (PRO) measure for clinical and research use. Use the MDASI to assess the severity of symptoms experienced by patients with cancer and the interference with daily living caused by these symptoms. The following parameters will be reported: 15c1a. Pain; 15c1b. Fatigue; 15c1c. Nausea; 15c1d. Disturbed sleep; 15c1e. Distress/feeling upset; 15c1f. Shortness of breath; 15c1g. Difficulty remembering; 15c1h. Lack of appetite; 15c1i. Drowsiness; 15c1j. Dry mouth; 15c1k. Sadness; 15c1l. Vomiting; 15c1m. Numbness/tingling; 15c1n. Walking; 15c1o. Activity; 15c1p. Working (including housework); 15c1q. Relations with other people; 15c1r. Enjoyment of life; 15c1s. Mood

    A total of eight quality of life parameters will be reported on each pediatric transplant patient.15c2a.Pain and Hurt 15c2b. Fatigue and Sleep 15c2c. Nausea 15c2d. Worry 15c2e. Nutrition 15c2f. Thinking 15c2g. Communication


  16. Relapse [ Time Frame: From start of therapy, assessed up to 24 months ]
    Will be calculated using the competing risk method as described by Gooley et al. (1999).

  17. Relapse-free survival [ Time Frame: From the start of treatment to the date of death, disease relapse, or last follow-up whichever occurs first, assessed up to 24 months ]
    Will be calculated using the Kaplan-Meier method.

  18. Time to neutrophil and platelet recovery/engraftment [ Time Frame: From day 0 to recovery or declaration of engraftment failure, assessed up to 24 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • This study is open to patients with acute myeloid leukemia (AML) evaluated within 30 days of the start of conditioning regimen and in first or second complete remission (CR)
  • Karnofsky performance status (KPS) >= 70%
  • The effects of radiation on the developing fetus are known to be teratogenic; for this reason, 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
  • Patients with acute myelogenous leukemia (AML) who are in first or second complete remission
  • All candidates for this study must have a human leukocyte antigen (HLA) (A,B,C,DR) identical sibling who is willing to donate primed blood stem cells (preferred) or bone marrow, or have a 10/10 allele matched unrelated donor; all ABO blood group combinations of the donor/recipient are acceptable
  • A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of >= 50% established by multi-gated acquisition scan (MUGA) or echocardiogram
  • Patients must have a serum creatinine of less than or equal to 1.3 mg/dL or creatinine clearance > 70ml/min as calculated by the Cockcroft-Gault formula
  • A bilirubin of less than or equal to 1.5mg/dL, excluding patients with Gilberts disease
  • Patients should also have a serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal
  • Pulmonary function tests including diffusing capacity of the lung for carbon monoxide (DLCO) will be performed; forced expiratory volume in 1 second (FEV 1) and DLCO should be greater than 50% of predicted normal value
  • All subjects must have the ability to understand and the willingness to sign a written informed consent; signed informed consent form approved by the Institutional Review Board (IRB) is required; the patient, family member, and transplant staff physician (physician, nurse, and social worker) meet at least once prior to starting the transplant procedure; during this meeting, all pertinent information with respect to risks and benefits to the donor and recipient will be presented; alternative treatment modalities will be discussed
  • The time from the end of last induction, re-induction, or consolidation regimen should be greater than or equal to 14 days
  • Prior therapy with etoposide and cyclophosphamide is allowed
  • DONOR: donor evaluation and eligibility will be assessed as per current City of Hope standard operating procedure (SOP)

Exclusion Criteria:

  • Patients should not have any uncontrolled illness including ongoing or active or poorly controlled infection
  • Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy; maintenance therapy with Food and Drug Administration (FDA)-approved targeted therapies (e.g. tyrosine kinase inhibitors for Philadelphia chromosome [Ph] positive [+] acute lymphoblastic leukemia [ALL], and FLT inhibitors for FLT3+ patients) will be allowed after day 60 disease assessment
  • Prior radiation therapy that would exclude the use of TMLI
  • Relapsed patients who have undergone autologous or allogeneic hematopoietic stem cell transplantation previously
  • Patients with psychological or medical condition that patient's physician deems unacceptable to proceed to allogeneic hematopoietic stem cell transplantation
  • Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50%
  • Patients who have been treated with chemotherapy or radiation for the purpose of induction, re-induction or consolidation, within two weeks of planned study enrollment
  • Patients with other active malignancies are ineligible for this study, other than localized malignancies
  • Patients that are pregnant or breastfeeding
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, including but not limited to, infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03467386


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Anthony S. Stein, MD    626-256-4673    astein@coh.org   
Principal Investigator: Anthony S. Stein, MD         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anthony Stein, MD City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03467386     History of Changes
Other Study ID Numbers: 17423
NCI-2018-00177 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17423 ( Other Identifier: City of Hope Medical Center )
First Posted: March 16, 2018    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Tacrolimus
Lenograstim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Adjuvants, Immunologic