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Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia

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ClinicalTrials.gov Identifier: NCT02094794
Recruitment Status : Recruiting
First Posted : March 24, 2014
Last Update Posted : March 19, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This phase II trial studies the safety and efficacy of total marrow and lymphoid irradiation (TMLI) in combination with two chemotherapy drugs, etoposide and cyclophosphamide, as a preparative regimen before donor stem cell transplant in treating patients with high-risk acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) who have failed previous therapy. Intensity-modulated radiation therapy (IMRT) uses imaging to provide a three-dimensional view of the area to be irradiated. Doctors can then shape and direct the radiation beams at the area from multiple directions while avoiding, as much as possible, nearby organs. TMLI is a method of using IMRT to direct radiation to the bone marrow. Radiation therapy is given before transplant to suppress the immune system, prevent rejection of the transplanted cells, and wipe out any remaining cancer cells. TMLI may allow a greater radiation dose to be delivered to the bone marrow as a preparative regimen before transplant while causing fewer side effects than standard radiation therapy.

Condition or disease Intervention/treatment Phase
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Drug: etoposide Drug: cyclophosphamide Radiation: total marrow irradiation Procedure: allogeneic hematopoietic stem cell transplantation Procedure: allogeneic bone marrow transplantation Other: Imaging Biomarker Analysis Phase 2

Detailed Description:

PRIMARY OBJECTIVES: I. Following a patient safety lead-in, evaluate the anti-tumor activity of the allogeneic hematopoietic cell transplant (alloHCT) preparative regimen - TMLI, cyclophosphamide (Cy) and etoposide (VP-16), as assessed by 2-year progression-free survival (PFS).

SECONDARY OBJECTIVES: I. Estimate overall survival (OS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

II. Evaluate early and late toxicities/complications by organ and severity, and characterize by organ dose/dose volume, including acute/chronic graft-versus-host-disease (GVHD), infection, and longer-term complications (via protocol #s 07173 and 00029).

Dual Energy Computed Tomography (DECT)/Water Fat Magnetic Resonance Imaging (WFMRI) Correlative Objectives (Optional):

I. Temporal assessment of treatment impact on bone marrow as measured by: change over time in cellularity and adiposity (bone marrow trephine hematoxylin and eosin [H&E]) and change over time of red marrow (cellularity) and yellow marrow (adipocyte) (water-fat MRI and dual energy CT).

II. Relative assessment of bone marrow status between TMLI and conventional total body irradiation (TBI).

III Correlation of DECT, MRI, imaging with biological samples (bone marrow biopsy) for cellularity/adiposity.

IV. Relative assessment of chimerism engraftment kinetics between TMLI and TBI.

3'-Deoxy-3'[^18F] Fluorothymidine (FLT)-Positron Emission Tomography (PET) Correlative Objectives (Optional): I. Feasibility of FLT-PET imaging biomarker as a predictor of treatment response.

II. Correlation of FLT-PET imaging with biological correlate for leukemia. III. Characterize relative distribution of leukemia in bone marrow (BM) environment.

OUTLINE: Patients undergo image guided TMLI on days -9 to -5, receive etoposide intravenously (IV) on day -4 and cyclophosphamide IV on day -2, and undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0.

After completion of study treatment, patients are followed up for 5 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 87 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Total Marrow and Lymphoid Irradiation (TMLI) Given in Combination With Cyclophosphamide and Etoposide as Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia
Study Start Date : April 29, 2014
Estimated Primary Completion Date : November 2018
Estimated Study Completion Date : November 2018


Arm Intervention/treatment
Experimental: Treatment (TMLI, chemotherapy)
Patients undergo image guided TMLI on days -9 to -5, receive etoposide IV on day -4 and cyclophosphamide IV on day -2, and undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0.
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Radiation: total marrow irradiation
Undergo TMLI

Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic peripheral blood stem cell or bone marrow transplant

Procedure: allogeneic bone marrow transplantation
Undergo allogeneic peripheral blood stem cell or bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow

Other: Imaging Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Incidence of toxicity, scored on both the Bearman Scale and National Cancer Institute Common Terminology Criteria version 4.03 (Safety lead-in segment) [ Time Frame: Up to 30 days after stem cell infusion ]
    Toxicity information recorded will include the type, severity, and the probable association with the study regimen.

  2. PFS [ Time Frame: The time from start of protocol therapy to death, relapse/progression, or last follow-up, whichever comes first, assessed up to 2 years ]
    Calculated using the Kaplan-Meier method. The cumulative incidence of relapse/progression will be calculated as a competing risk using the Gray method.


Secondary Outcome Measures :
  1. OS [ Time Frame: The time from start of protocol therapy to death, or last follow-up, whichever comes first, assessed up to 5 years ]
    Calculated using the Kaplan-Meier method.

  2. Time to relapse/progression [ Time Frame: From start of therapy to time of relapse/progression, assessed up to 5 years ]
    Calculated using the Kaplan-Meier method.

  3. Complete response (CR) proportion [ Time Frame: The start of therapy to the time of CR, assessed at day 30 ]
  4. NRM [ Time Frame: From start of therapy until non-disease related death, or last follow-up, whichever comes first, assessed up to 5 years ]
    Calculated using the Kaplan-Meier method. The cumulative incidence of non-relapse mortality will be calculated as a competing risk using the Gray method.

  5. Incidence of infection [ Time Frame: Up to 100 days post-transplant ]
    Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any.

  6. Incidence of toxicities, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: Up to day 100 post-transplant ]
    The worst grade of all toxicities will be collected from day -9 to day -1 and again from day 0 to day 30 post-transplant. From day 31 to 100 post-transplant only grade 3, 4 and 5 toxicities will be collected. Toxicity information recorded 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. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

  7. Incidence of acute GVHD (aGVHD) of grades 2-4, graded according to the Consensus Grading [ Time Frame: Up to day 100 post-transplant ]
    The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

  8. Incidence of aGVHD of grades 3-4, graded according to the Consensus Grading [ Time Frame: Up to day 100 post-transplant ]
    The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

  9. Incidence of chronic GVHD, scored according to National Institute of Health Consensus staging [ Time Frame: Up to 5 years ]


Information from the National Library of Medicine

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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:

  • Participant has the ability and the willingness to sign the informed consent document (for adults only, for participants with mild cognitive abilities may use a legally authorized representative)
  • Documented (signed) informed consent; 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 donor and recipient will be presented; alternative treatment modalities will be discussed:

    • A. No Research Imaging - for patients for whom one or more of the following applies:

      • Is a minor (< 18 years of age)
      • Acute lymphoblastic leukemia (ALL) diagnosis
      • Does not agree to optional imaging (WF-MRI, DECT)
    • B. With Research Imaging - all of the following must apply:

      • Adult (>= 18 years of age)
      • Acute myeloid leukemia AML diagnosis
      • Agree to optional imaging: WF-MRI and DECT
      • Do not agree to optional FLT-PET, or there are no FLT-PET slots available
    • C. With Research Imaging plus FLT-PET

      • Adult (>= 18 years of age)
      • AML diagnosis
      • Agrees to optional imaging: WF-MRI and DECT
      • Agrees to optional FLT-PET
      • FLT-PET accrual remains open
  • Karnofsky performance status >= 70% =< 2
  • Acute lymphocytic leukemia or acute myelogenous leukemia who are not in first remission or second remission i.e. after failing induction therapy, or in relapse or beyond second remission; (prior therapy with VP-16 and Cytoxan is allowed)
  • All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical siblings who is willing to donate bone marrow or primed blood stem cells or a 10/10 allele matched unrelated donor; a single allele mismatch at A, B, C, DR or DQ and a killer immunoglobulin-like receptor (KIR) mismatch at C will be allowed; all ABO blood group combinations of the donor/recipient are acceptable
  • The time from the end last induction, re-induction, or consolidation regimen should be greater than or equal to 14 days from planned start of study treatment; Note: Chemotherapy given within 14 days of planned study enrollment for the purpose of controlling counts is permitted
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) OR 3 x ULN for Gilbert's disease
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 5 x ULN
  • Measured creatinine clearance >= 40 ml/min per 24 hour urine collection OR serum creatinine =< 1.3 mg/dL
  • Women of child bearing potential only: Negative urine or serum pregnancy test
  • Pulmonary function tests: Forced expiratory volume in one second (FEV1) and carbon monoxide diffusion capacity (DLCO) (adjusted for Hb) >= 50% adjusted of predicted normal value
  • Echocardiogram (ECHO) or multi gated acquisition scan (MUGA): ejection fraction of >= 50% AND no finding of abnormal wall motion (i.e. report does not indicate that wall motion is "abnormal" or "altered")
  • Electrocardiogram (EKG) showing no ischemic changes and no abnormal rhythm
  • Agreement of men AND women-of-child-bearing-potential 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
  • DONOR ELIGIBILITY: Donor evaluation and eligibility will be assessed as per current City of Hope standard operating procedure (SOP)

Exclusion Criteria:

  • Prior autologous or allogeneic hematopoietic stem cell
  • Prior radiation therapy that would exclude the use of TMLI
  • Plans during the trial to receive any other (non-trial) investigational agents, or concurrent biological, chemotherapy, or radiation therapy; (chemotherapy for white blood count control is permitted)
  • Uncontrolled illness including ongoing or active infection
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to etoposide
  • Patients with other active malignancies are ineligible for this study, other than localized malignancies
  • Patients with psychological or medical condition that patient's physician deems unacceptable to proceed to allogeneic hematopoietic stem cell transplantation
  • Women who are planning to become pregnant or breast feed during the trial
  • Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

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): NCT02094794


Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Anthony S. Stein    800-826-4673      
Principal Investigator: Anthony S. Stein         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Anthony Stein City of Hope Medical Center

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02094794     History of Changes
Other Study ID Numbers: 14012
NCI-2014-00639 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
14012 ( Other Identifier: City of Hope Medical Center )
R01CA154491 ( U.S. NIH Grant/Contract )
First Posted: March 24, 2014    Key Record Dates
Last Update Posted: March 19, 2018
Last Verified: March 2018

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Etoposide phosphate
Etoposide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors