Clinical trial NCT00800150: Total Marrow and Total Lymph Node Irradiation, Fludarabine, and Melphalan Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Hematological Cancer That Has Not Responded to Treatment
Official title: Phase I Study of Escalating Doses of Radiation Therapy Using Helical Tomotherapy in Combination With Fludarabine (FLU) and Melphalan (MEL) as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell (HSC) Transplantation in Patients With Advanced and Hematological Malignancies Who Are Not Eligible for Fully Myeloablative Regimen
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities
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 adult T-cell leukemia/lymphoma
secondary acute myeloid leukemia
stage III adult T-cell leukemia/lymphoma
stage IV adult T-cell leukemia/lymphoma
adult grade III lymphomatoid granulomatosis
adult nasal type extranodal NK/T-cell lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
splenic marginal zone lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage III mycosis fungoides/Sezary syndrome
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
stage IV mycosis fungoides/Sezary syndrome
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent mycosis fungoides/Sezary syndrome
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
intraocular lymphoma
primary central nervous system non-Hodgkin lymphoma
primary myelofibrosis
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
myelodysplastic/myeloproliferative neoplasm, unclassifiable
cutaneous B-cell non-Hodgkin lymphoma
Waldenstrom macroglobulinemia
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-12-01
Enrollment: 6
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving total marrow and total lymph node irradiation together with low doses of chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect).

PURPOSE: This phase I trial is studying the side effects and best dose of total marrow and total lymph node irradiation when given together with fludarabine and melphalan followed by donor stem cell transplant in treating patients with advanced hematological cancer that has not responded to treatment.

Detailed description: OBJECTIVES:

Primary

* To determine the maximum tolerated dose of intensity-modulated total marrow and lymph node irradiation (TMLI) using helical tomotherapy in combination with a reduced-intensity preparative regimen comprising fludarabine phosphate and melphalan in patients undergoing allogeneic hematopoietic stem cell transplantation for advanced, relapsed or refractory hematological malignancies.
* To describe the toxicities of escalating doses of TMLI in these patients.

Secondary

* To describe the frequency of clinical response in patients treated with this regimen.
* To describe the frequency of primary and secondary engraftment failure in patients treated with this regimen.
* To describe the time to neutrophil and platelet engraftment in patients treated with this regimen.
* To describe the incidence of acute and chronic graft-versus-host disease in patients treated with this regimen.
* To describe the overall survival of patients treated with this regimen.
* To describe the progression-free survival of patients treated with this regimen.

OUTLINE: This is a dose-escalation study of intensity-modulated total marrow and lymph node irradiation (TMLI).

* Intensity-modulated radiation therapy: Patients undergo TMLI to skeletal bone/marrow, major lymph node chains, spleen, and liver using helical tomotherapy twice daily on days -6 to -3.
* Reduced-intensity preparative regimen: Patients receive fludarabine phosphate IV on days -6 to -2 and melphalan IV on day -1.
* Hematopoietic stem cell transplantation (HSCT): Patients undergo allogeneic HSCT on day 0.

After completion of study treatment, patients are followed periodically.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histopathologically confirmed diagnosis of 1 of the following:

  * Acute myeloid leukemia (AML)
  * Myelodysplastic syndromes

    * Intermediate- or high-risk disease
  * Myelofibrosis
  * Granulocytic sarcoma (chloroma)

    * With or without bone marrow involvement
  * Mixed lineage leukemia

    * Induction therapy must have been directed predominantly against AML
  * Acute lymphoblastic leukemia
  * Non-Hodgkin lymphoma
  * Multiple myeloma
* Relapsed or refractory disease with M3 marrow (marrow blasts \> 25%), meeting 1 of the following criteria:

  * Persistent disease after an induction attempt
  * Persistent initial disease after two induction attempts
  * Relapse after one re-induction attempt (second relapse)
  * Persistent disease after first relapse and initial re-induction attempt
* Not eligible for myeloablative allogeneic hematopoietic stem cell transplantation due to age (\> 50 years), organ insufficiency, or significant comorbidity

  * Patients 16-50 years of age must meet ≥ 1 of the following criteria:

    * Ejection fraction 50-60% by MUGA scan and/or echocardiogram
    * DLCO 50-75% of predicted
    * Creatinine clearance or GFR 60-80 mL/min
    * Serum bilirubin ≤ 2.0 mg/dL
    * SGOT and SGPT 1.5-5 times upper limit of normal
    * No other medical and/or psychosocial problem that, in the opinion of the primary physician or principal investigator, would place the patient at unacceptable risk from study regimen
* No Fanconi anemia
* HLA-identical sibling OR matched unrelated donor available

PATIENT CHARACTERISTICS:

* Zubrod or Karnofsky performance status 70-100%
* Negative pregnancy test
* Able to lie supine in a full body cast for 30 minutes
* No HIV infection
* No evidence of active hepatitis B or C infection
* No evidence of cirrhosis
* No uncontrolled viral, bacterial, or fungal infection within the past 4 weeks
* No radiographic changes indicating pulmonary disease (e.g., pulmonary nodules, infiltrates, or pleural effusion) unless cleared by pulmonary biopsy that shows no evidence of active pulmonary disease
* No major medical or psychiatric disorder that would seriously compromise patient tolerance of study regimen

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior radiation therapy

Primary outcomes:
measure: Maximum tolerated dose of intensity-modulated total marrow and lymph node irradiation using helical tomotherapy
measure: Toxicity
Secondary outcomes:
measure: Frequency of clinical response
measure: Frequency of primary and secondary engraftment failure
measure: Time to neutrophil and platelet engraftment
measure: Incidence of acute and chronic graft-versus-host disease
measure: Overall survival
measure: Progression-free survival
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
Study officials:
affiliation: City of Hope Comprehensive Cancer Center
name: Joseph Rosenthal, MD
role: PRINCIPAL_INVESTIGATOR
References: