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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT02094794
First received: March 20, 2014
Last updated: August 15, 2014
Last verified: August 2014
  Purpose

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 Intervention 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
Drug: etoposide
Drug: cyclophosphamide
Radiation: total marrow irradiation
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: allogeneic bone marrow transplantation
Procedure: peripheral blood stem cell transplantation
Radiation: fludeoxyglucose F 18
Procedure: positron emission tomography
Procedure: computed tomography
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    Toxicity information recorded will include the type, severity, and the probable association with the study regimen.

  • 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 ] [ Designated as safety issue: No ]
    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:
  • OS [ Time Frame: The time from start of protocol therapy to death, or last follow-up, whichever comes first, assessed up to 5 years ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method.

  • Time to relapse/progression [ Time Frame: From start of therapy to time of relapse/progression, assessed up to 5 years ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method.

  • Complete response proportion [ Time Frame: The start of therapy to the time of CR, assessed at day 30 ] [ Designated as safety issue: No ]
  • NRM [ Time Frame: From start of therapy until non-disease related death, or last follow-up, whichever comes first, assessed up to 5 years ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method. The cumulative incidence of non-relapse mortality will be calculated as a competing risk using the Gray method.

  • Incidence of infection [ Time Frame: Up to 100 days post-transplant ] [ Designated as safety issue: No ]
    Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any.

  • Incidence of toxicities, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to day 100 post-transplant ] [ Designated as safety issue: Yes ]
    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.

  • Incidence of acute GVHD (aGVHD) of grades 2-4, graded according to the Consensus Grading [ Time Frame: Up to day 100 post-transplant ] [ Designated as safety issue: No ]
    The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

  • Incidence of aGVHD of grades 3-4, graded according to the Consensus Grading [ Time Frame: Up to day 100 post-transplant ] [ Designated as safety issue: No ]
    The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

  • Incidence of chronic GVHD, scored according to National Institute of Health Consensus staging [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 46
Study Start Date: April 2014
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic peripheral blood stem cell or bone marrow transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Radiation: fludeoxyglucose F 18
Correlative studies
Other Names:
  • 18FDG
  • FDG
Procedure: positron emission tomography
Correlative studies
Other Names:
  • FDG-PET
  • PET
  • PET scan
  • tomography, emission computed
Procedure: computed tomography
Correlative studies
Other Name: tomography, computed

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. Summarize toxicities/complications by organ and severity, including acute/chronic graft-versus-host disease (GVHD), and infection.

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.

  Eligibility

Ages Eligible for Study:   16 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • Karnofsky performance status (KPS) >= 70%
  • 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 lymphocytic leukemia or acute myelogenous leukemia who are not in first remission or second remission i.e. after failing remission induction therapy or in relapse or beyond second remission
  • 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 KIR mismatch at C will be allowed; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques (red cell exchange or plasma exchange)
  • Prior therapy with VP-16 and Cytoxan is allowed
  • 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 > 80 ml/min
  • A bilirubin of less than or equal to 1.5 mg/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 diffusion capacity of the lung for carbon monoxide (DLCO) will be performed; forced expiratory volume of the lung in one second (FEV1) and DLCO should be greater than 50% of predicted normal value
  • The time from the end last induction or re-induction attempt should be greater than or equal to 14 days
  • 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 donor and recipient will be presented; alternative treatment modalities will be discussed; the risks are explained in detail in the enclosed consent forms
  • The time from the end of last induction or re-induction regimen should be greater than or equal to 14 days

Exclusion Criteria:

  • Patients should not have any uncontrolled illness including ongoing or active infection
  • Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to etoposide
  • 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 patients 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 within two weeks of planned study enrollment
  • Patients with other active malignancies are ineligible for this study, other than localized malignancies
  • Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02094794

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Anthony S. Stein    800-826-4673    becomingapatient@coh.org   
Principal Investigator: Anthony S. Stein         
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Anthony Stein City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02094794     History of Changes
Other Study ID Numbers: 14012, NCI-2014-00639, 14012
Study First Received: March 20, 2014
Last Updated: August 15, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Cyclophosphamide
Etoposide
Etoposide phosphate
Fluorodeoxyglucose F18
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Diagnostic Uses of Chemicals
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Radiopharmaceuticals
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014