Combination Chemotherapy and Peripheral Blood Stem Cell Transplant Followed By Aldesleukin and Sargramostim in Treating Patients With Inflammatory Stage IIIB or Metastatic Stage IV Breast Cancer

Phase 2

Completed

Conditions: Estrogen Receptor-negative Breast Cancer
Male Breast Cancer
Estrogen Receptor-positive Breast Cancer
Progesterone Receptor-negative Breast Cancer
Inflammatory Breast Cancer
Progesterone Receptor-positive Breast Cancer
Stage IIIB Breast Cancer
Stage IV Breast Cancer

Interventions: Drug: tamoxifen citrate
Drug: busulfan
Drug: thiotepa
Drug: melphalan
Biological: aldesleukin
Biological: sargramostim
Procedure: peripheral blood stem cell transplantation
Radiation: radiation therapy

Registration Number: NCT00003199

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase II trial studies how well giving combination chemotherapy and peripheral blood stem cell transplant followed by aldesleukin and sargramostim works in treating patients with inflammatory stage IIIB or metastatic stage IV breast cancer. Drugs used in chemotherapy, such as busulfan, melphalan, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. This may allow more chemotherapy to be given so that more tumor cells are killed. Aldesleukin may stimulate the white blood cells to kill breast cancer cells. Giving aldesleukin together with sargramostim may kill more tumor cells

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the event-free survival and survival of patients treated for inflammatory (Stage IIIb) and responsive stage IV breast cancer with BUMELTT and PBSC support and low dose immunotherapy with IL2 and GM-CSF.

SECONDARY OBJECTIVES:

II. To determine the toxicity of a combination of low-dose IL-2 and GM-CSF in patients following HDC with BUMELTT and PBSC support.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive busulfan orally (PO) once every 6 hours on days -8, -7, and -6; melphalan IV over 30 minutes on days -5 and -4; and thiotepa IV over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell infusion on day 0.

POST-TRANSPLANT THERAPY: All patients receive tamoxifen citrate\* PO once daily beginning prior to aldesleukin (IL-2) and sargramostim (GM-CSF) therapy and continuing for 5 years or until relapse (estrogen receptor \[ER\]- or progesterone receptor \[PR\]-positive patients) OR until completion of IL-2/GM-CSF therapy (ER-negative or PR-negative patients). Eligible patients receive IL-2 subcutaneously (SC) daily and GM-CSF SC 3 times weekly for 12 weeks beginning 30-100 days after transplantation. Patients may receive radiotherapy after completion of IL-2/GM-CSF treatment if no prior radiotherapy was given before transplantation.

\*Stage IV patients not receiving IL-2/GM-CSF therapy who received tamoxifen citrate as part of adjuvant therapy and subsequently failed, receive oral anastrozole once daily for 5 years or until progression instead of tamoxifen.

\[\*For postmenopausal patients, the choice and duration of hormonal therapy given in addition to or an alternative to tamoxifen therapy will be at the physician's discretion\]

Patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

Patients with inflammatory (stage IIIb) or responsive stage IV breast cancer with metastasis to soft tissue and/or bone; responsive stage IV disease is defined as patients who achieve a PR (>= 50% reduction in measurable tumor burden) or CR following initial chemotherapy for metastatic disease or patients with locally recurrent disease (chest wall/axillary nodes) who are rendered disease-free following surgery or radiation therapy without receiving chemotherapy; bone disease is categorized as responsive if there is demonstrated sclerosis of prior lesions with no new lesions
Patients should have received 4-7 cycles of an Adriamycin and/or taxane-based regimen for stage IIIb or stage IV disease; locally recurrent (chest wall/axillary nodes) patients rendered NED by RT or surgery do not need to receive chemotherapy for stage IV disease prior to Cytoxan/Taxol
Patient has received Cytoxan 4 gm/m^2 x 1 and Taxol 250 mg/m^2 x 1 per FHCRC protocol 506.03; Cytoxan/Taxol must be given after all other chemotherapy is completed and before transplant
Stem cells were collected after mobilization with Cytoxan/Taxol or after mobilization from an FHCRC approved cytokine protocol; if syngeneic collection, PBSC's were collected by using G-CSF according to FHCRC protocol 753; patient has an adequate number of peripheral blood stem cells stored (>= 2.5 x 10^6 CD34+ cells/kg)
The patient must have the capacity to give informed consent; the patient must have signed an approved consent form conforming with federal and institutional guidelines
Hepatic function: Bilirubin =< 2 mg%; SGOT or SGPT =< 2.5 x institutional normal
Renal function: Creatinine =< 2.0 mg/dl or a creatinine clearance >= 50 mg/min
Pre-Study tests have been performed as outlined in the Study Calendar
Patients will begin IL-2/GM-CSF therapy if they meet the following criteria post-transplant:
Can start therapy 30 to 100 days after transplant
Karnofsky performance status > 60
ANC > 1,000 cells/mm^3 and platelets > 30,000/cells/mm^3 (transfusion independent) for at least 5 days before starting therapy
Total bilirubin =< 2.5 x upper limit of normal
SGOT =< 2.5 x upper limit of normal
Creatinine =< 2.0 mg/dl

Exclusion Criteria

Patients with a Karnofsky Performance Score less than 70
Patients with a left ventricular ejection fraction less than 50 % (LVEF must be performed in patients with symptoms of CHF, abnormal cardiac exam or history of Adriamycin therapy total dose > 400 mg/m^2)
Patient is pregnant
Patient is seropositive for the human immunodeficiency virus
Patients with a history of seizures
Patients with hypersensitivity to E.coli preparations
Patients with active auto-immune disease
Patients with clinically significant pulmonary disease, i.e., diffusion capacity corrected < 60% of predicted; patients with pulmonary problems should be evaluated with appropriate pulmonary studies and/or consult
Patients with a history of CNS lesion (brain or carcinoid meningitis)
Patients with significant active infection precluding transplant
Patients who have had more than one prior chemotherapy regimen for stage IV disease or a prior transplant for any stage disease
Patients who have had CD34+ selection of their PBSC products
Patients will not receive IL-2/GM-CSF therapy if they:
Are > 100 days from transplant
Have documented disease progression after transplant
Have an active infection
Manifested cardiac complications during the initial transplant period, including arrhythmias (that required therapy), congestive heart failure, angina, myocardial infarct, or decreased LVEF to < 45%
Currently have pericardial effusions, pleural effusions or ascites
Manifested pulmonary toxicity during the initial transplant period and have a diffusion capacity corrected =< 60%
Are on steroids
Currently have a Grade 3 toxicity from BuMelTT
If the patient does not wish to receive the therapy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	tamoxifen citrate	See Detailed Description.
Arm I	aldesleukin	See Detailed Description.
Arm I	sargramostim	See Detailed Description.
Arm I	peripheral blood stem cell transplantation	See Detailed Description.
Arm I	radiation therapy	See Detailed Description.
Arm I	busulfan	See Detailed Description.
Arm I	thiotepa	See Detailed Description.
Arm I	melphalan	See Detailed Description.

Primary Outcome Measures

Name	Time	Method
Event-free Survival	11 years	Event-free survival of patients treated for inflammatory (Stage IIIb) and responsive stage IV breast cancer with BUMELTT and PBSC support and low dose immunotherapy with IL2 and GM-CSF.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Toxicity of a Combination of Low-dose IL-2 and GM-CSF	16 Weeks	IL-2/GM-CSF toxicity assessed using the NCI Toxicity Criteria. Toxicity was defined as any grade 2, 3, 4 or 5 CNS (except grade 0-3 malaise and fatigue) toxicity; any grade 3, 4, or 5 non-CNS or non-hematological toxicity (except grade 0-3 bilirubin); or any grade 4 or 5 hematological toxicity.
Overall Survival	11 years	Overall survival of patients treated for inflammatory (Stage IIIb) and responsive stage IV breast cancer with BUMELTT and PBSC support and low dose immunotherapy with IL2 and GM-CSF.