Clinical trial NCT00006042: Cyclophosphamide Plus Bone Marrow Transplantation in Treating Patients With Hematologic Cancer
Official title: Non-Myeloablative Allogeneic Bone Marrow Transplantation for Hematologic Malignancies Using Haploidentical Donors: A Phase I Trial of Pre-Transplant Cyclophosphamide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Keywords: recurrent adult Hodgkin lymphoma
Burkitt lymphoma
refractory multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
recurrent childhood lymphoblastic lymphoma
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
refractory chronic lymphocytic leukemia
chronic phase chronic myelogenous leukemia
adult acute myeloid leukemia in remission
adult acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission
recurrent/refractory childhood Hodgkin lymphoma
stage II adult lymphoblastic lymphoma
stage III grade 3 follicular lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III adult Burkitt lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV adult Burkitt lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult Burkitt lymphoma
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
recurrent childhood small noncleaved cell lymphoma
recurrent childhood large cell lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
recurrent mantle cell lymphoma
childhood chronic myelogenous leukemia
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage III marginal zone lymphoma
stage IV small lymphocytic lymphoma
stage IV marginal zone lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
adult acute myeloid leukemia with t(8;21)(q22;q22)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with t(15;17)(q22;q12)
childhood myelodysplastic syndromes
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Sex: ALL
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Bone marrow transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy used to kill cancer cells.

PURPOSE: Phase I trial to study the effectiveness of cyclophosphamide plus bone marrow transplantation in treating patients who have hematologic cancer.

Detailed description: OBJECTIVES:

* Determine the minimum effective dose of pretransplant cyclophosphamide to induce engraftment of haploidentical allogeneic bone marrow without the use of myeloablative conditioning in patients with hematologic malignancies.
* Determine the incidence and severity of graft versus host disease and nonhematologic toxicities with this treatment regimen in these patients.
* Correlate the pretreatment phenotypic and functional immunologic characteristics in these patients in relation to risk of graft rejection with this treatment regimen.

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

Patients receive fludarabine IV over 1 hour on days -6 to -2; cyclophosphamide IV over 1 hour on days -6, -5, and 3; total body irradiation on day -1; and allogeneic bone marrow transplantation on day 0. Patients also receive tacrolimus IV or orally twice a day on days 4-50; oral mycophenolate mofetil on days 4-35; and filgrastim (G-CSF) subcutaneously or IV starting on day 4 and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of cyclophosphamide until the minimum effective dose necessary to induce chimerism without unacceptable toxicity in these patients is determined.

Patients are followed at 2 and 6 months, at one year, and then annually thereafter.

PROJECTED ACCRUAL: At least 23 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Patients with any of the following diagnoses:

  * Chronic myelogenous leukemia

    * Chronic phase 1

      * Failed prior interferon alfa therapy OR
      * Relapsed after prior autologous stem cell transplantation
    * Chronic phase 2
  * Acute leukemia

    * Standard risk

      * Age over 60 years
      * Complete remission 1 (CR1)
    * High risk

      * High WBC at presentation, unfavorable cytogenetics, mixed lineage, delayed response to induction chemotherapy
      * CR1
      * Complete remission 2 or higher
  * Acute lymphocytic leukemia

    * CR1 or higher
  * Myelodysplastic syndrome

    * Untreated OR
    * CR1
  * Acute myeloid leukemia in CR1
  * Chronic lymphocytic leukemia

    * Rai stage III or IV OR
    * Received prior autologous stem cell transplantation
  * Multiple myeloma

    * Stage II or III
    * Stable or progressive disease after prior chemotherapy OR
    * Received prior autologous stem cell transplantation
  * Non-Hodgkin's Lymphoma
  * Hodgkin's lymphoma
* Ineligible for or refused autologous or standard allogeneic bone marrow transplantation
* Ineligible for bone marrow transplantation from an HLA matched, sibling donor or from an HLA matched, unrelated donor
* Must have an HLA mismatched, related donor (3-5 out of 6)

PATIENT CHARACTERISTICS:

Age:

* 0.5 to 70

Performance status:

* ECOG 0-1

Life expectancy:

* Not specified

Hematopoietic:

* Not specified

Hepatic:

* Bilirubin less than 3.1 mg/dL

Renal:

* Not specified

Cardiovascular:

* Left ventricular ejection fraction at least 35%

Pulmonary:

* FEV_1 and FVC at least 40% of predicted OR
* FEV_1 and FVC at least 60% in patients who have received prior thoracic or mantle radiotherapy

Other:

* HIV negative
* No other debilitating medical or psychiatric illness that would preclude study compliance
* Not pregnant
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* See Disease Characteristics
* No prior transfusions from donor

Chemotherapy:

* See Disease Characteristics

Endocrine therapy:

* Not specified

Radiotherapy:

* Not specified

Surgery:

* Not specified

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Ephraim J. Fuchs, MD
role: STUDY_CHAIR
References:
citation: O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M, Rhubart P, Cowan K, Piantados S, Fuchs EJ. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8(7):377-86. doi: 10.1053/bbmt.2002.v8.pm12171484.