Clinical trial NCT00074269: Allogeneic Stem Cell Transplant After ATG, High-Dose Melphalan, and Fludarabine for Patients With Breast Cancer
Official title: Pilot Study Of Allogeneic Peripheral Blood Progenitor Cell Transplantation In Patients With Chemotherapy-Refractory Or Poor-Prognosis Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: recurrent breast cancer
stage IV breast cancer
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-12-11
Enrollment: 5
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy, such as fludarabine and melphalan, before a donor peripheral blood stem cell transplant helps stop the growth of tumor cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining tumor cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin, cyclosporine, and methotrexate before or after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well antithymocyte globulin, high-dose melphalan, fludarabine, and allogeneic peripheral stem cell transplant work in treating patients with metastatic adenocarcinoma of the breast.

Detailed description: OBJECTIVES:

Primary

* Determine the toxicity and tolerability of allogeneic peripheral blood stem cell transplantation after a nonmyeloablative preparative regimen comprising anti-thymocyte globulin, high-dose melphalan, and fludarabine in women with chemotherapy-refractory or poor-prognosis metastatic adenocarcinoma of the breast.
* Determine the ability of this preparative regimen to facilitate long-term engraftment of allogeneic stem cells and lymphocytes in these patients.
* Determine the response in measurable/evaluable disease and its temporal relationship to the preparative chemotherapy used and to the onset of clinical graft-versus-host disease (GVHD) in patients treated with this regimen.

Secondary

* Determine the progression-free and overall survival of patients treated with this regimen.
* Determine the tumor response and its temporal relationship to administration of high-dose chemotherapy and to the onset of GVHD in patients treated with this regimen.
* Determine the frequency and durability of the induction of full donor chimerism of lymphocytes in patients treated with this regimen.

OUTLINE: This is a nonrandomized, pilot study.

* Nonmyeloablative preparative regimen: Patients receive fludarabine IV over 30 minutes on days -8 to -4, anti-thymocyte globulin IV over 4 hours on days -7 to -4, and high-dose melphalan IV over 30 minutes on days -3 and -2.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV (and then orally when tolerated) every 12 hours beginning on day -4 and tapered after day 42 (if no GVHD occurs) or after day 90 (if grade I acute GVHD occurs). Patients also receive methotrexate IV on days 1, 3, and 6.
* Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 0 and continuing until blood counts recover.
* Donor lymphocyte infusion (DLI): Patients who show disease progression or fail to achieve full donor type T-cell chimerism (at least 90% donor derived T-cells) by the 90-day assessment posttransplantation, and have no evidence of active GVHD may receive DLI. Patients who have unresponsive disease with no active GVHD receive subsequent DLIs every 6-8 weeks.

Patients are followed at 1, 3, 6, 12, 18, 24, 30, and 36 months.

PROJECTED ACCRUAL: A total of 10 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed adenocarcinoma of the breast

  * Metastatic disease
* Meets 1 of the following criteria:

  * Chemotherapy-unresponsive disease defined as 1 of the following:

    * Less than a partial response to 2 consecutive chemotherapy regimens that included an anthracycline and a taxane in combination or succession
    * Progression of disease during or within 3 months of completion of a taxane, anthracycline, or platinol-based regimen
  * Histologically confirmed tumor involvement on bone marrow biopsy
* Measurable or evaluable disease\* defined as the following:

  * Bidimensionally reproducible measurable mass by physical examination, ultrasonography, radiography, CT scan, or MRI
  * Evaluable lesions apparent on clinical exam, x-ray, CT scan, or MRI which do not fit the criteria for measurability (e.g., ill-defined post-surgical masses or masses assessable in 1 dimension only)

    * Elevation of biological markers (e.g., CA 27.29) is considered evaluable disease NOTE: \*Bone lesions or pleural or peritoneal effusion alone are not considered measurable or evaluable disease
* Appropriate candidate for allogeneic stem cell transplantation
* No active CNS metastases
* Available HLA-identical sibling donor

  * 6/6 antigen match
  * Donor CD34 cells at least 2 times 10\^6/kg recipient weight
* Hormone receptor status:

  * Estrogen receptor negative or positive

    * Estrogen receptor positive tumors must demonstrate progression on at least 1 hormonal manipulation

PATIENT CHARACTERISTICS:

Age

* 18 to 60

Sex

* Female

Menopausal status

* Not specified

Performance status

* Karnofsky 70-100% OR
* ECOG 0-1

Life expectancy

* Not specified

Hematopoietic

* WBC at least 1,500/mm\^3
* Platelet count at least 30,000/mm\^3

Hepatic

* Bilirubin less than 3 times normal\*
* AST and ALT less than 3 times normal\* NOTE: \*Unless abnormality due to malignancy

Renal

* Creatinine no greater than 1.6 mg/dL

Cardiovascular

* LVEF greater than 40% by echocardiography or MUGA
* No myocardial infarction within the past 6 months

Pulmonary

* DLCO greater than 40% of predicted

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* HIV negative
* No serious localized or systemic infection
* No hypersensitivity to E. coli-derived products
* No history of non-breast malignant disease within the past 5 years except completely excised nonmelanoma skin cancer or carcinoma in situ of the cervix
* No chronic inflammatory disorder requiring concurrent glucocorticosteroids or other immunosuppressive medication
* No psychological condition or social situation that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Not specified

Chemotherapy

* See Disease Characteristics

Endocrine therapy

* No concurrent glucocorticoids

Radiotherapy

* No prior radiotherapy to an indicator lesion unless the lesion shows evidence of progression after discontinuation of the therapy

Surgery

* Not specified

Other

* No concurrent immunosuppressive medication

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 5 years post transplant
measure: Number of Participants With Long-term Engraftment of Allogeneic Stem Cells and Lymphocytes
timeFrame: 30 days post transplant
measure: Number of Participants With Acute and Chronic Graft-versus-host Disease (GVHD)
timeFrame: 100 days post transplant
Secondary outcomes:
measure: Progression-free Survival
timeFrame: From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
measure: Overall Survival
timeFrame: 1 year from the time of transplant
measure: Response as Measured at 12 Months Post Allografting
timeFrame: From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months
measure: Frequency of the Induction of Full Donor Chimerism of Lymphocytes as Measured at 1 Month Post Allografting
timeFrame: 1 month post allografting
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
Study officials:
affiliation: University of California, San Diego
name: Edward D. Ball, MD
role: PRINCIPAL_INVESTIGATOR
References: