Allogeneic Stem Cell Transplant After ATG, High-Dose Melphalan, and Fludarabine for Patients With Breast Cancer

Pilot Study Of Allogeneic Peripheral Blood Progenitor Cell Transplantation In Patients With Chemotherapy-Refractory Or Poor-Prognosis Metastatic Breast Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: methotrexate; Biological: anti-thymocyte globulin; Biological: therapeutic allogeneic lymphocytes; Drug: fludarabine phosphate; Procedure: peripheral blood stem cell transplantation; Biological: filgrastim; Drug: melphalan; Drug: cyclosporine; Biological: graft-versus-tumor induction therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0658
      • Rebecca and John Moores UCSD Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment	Drug: methotrexate; Biological: anti-thymocyte globulin; Biological: therapeutic allogeneic lymphocytes; Drug: fludarabine phosphate; Procedure: peripheral blood stem cell transplantation; Biological: filgrastim; Drug: melphalan; Drug: cyclosporine; Biological: graft-versus-tumor induction therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events		5 years post transplant
Number of Participants With Acute and Chronic Graft-versus-host Disease (GVHD)		100 days post transplant
Number of Participants With Long-term Engraftment of Allogeneic Stem Cells and Lymphocytes	Long-term Engraftment of Allogeneic Stem Cells and Lymphocytes based on cell counts of ANC >1000 for 3 consecutive days and platelet count of >50,000	30 days post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression assessed by CT scan	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
Overall Survival		1 year from the time of transplant
Frequency of the Induction of Full Donor Chimerism of Lymphocytes as Measured at 1 Month Post Allografting		1 month post allografting
Response as Measured at 12 Months Post Allografting	response (partial and complete) assessed by CT scan at 12 months post allografting	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

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Edward D. Ball, MD, University of California, San Diego

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: December 10, 2003
• First Submitted That Met QC Criteria: December 10, 2003
• First Posted (Estimated): December 11, 2003

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Melphalan; Fludarabine; Fludarabine phosphate; Methotrexate; Antilymphocyte Serum; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 020815; CDR0000343758 (Registry Identifier: PDQ (Physician Data Query))