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

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00003199
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 50
• Location: 1
• Arm: 1
• Actual Duration (Months): 145
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; Inflammatory Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIB Breast Cancer; Stage IV Breast Cancer	Drug: tamoxifen citrate; Drug: busulfan; Drug: thiotepa; Drug: melphalan; Biological: aldesleukin; Biological: sargramostim; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial for Patients With Inflammatory (Stage IIIB) and Responsive Metastatic Stage IV Breast Cancer Using Busulfan, Melphalan and Thiotepa Followed by Autologous or Syngeneic PBSC Rescue and 12 Weeks of Post-Engraftment Immunotherapy With Low-Dose IL-2 and GM-CSF
• Actual Study Start Date: Nov 1, 1997
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I See Detailed Description.

Drug: tamoxifen citrate; Given orally; Other Names: Nolvadex TAM tamoxifen TMX ; Drug: busulfan; Given orally; Other Names: BSF BU Misulfan Mitosan Myeloleukon ; Drug: thiotepa; Given IV; Other Names: Oncotiotepa STEPA TESPA Tespamin TSPA ; Drug: melphalan; Given IV; Other Names: Alkeran CB-3025 L-PAM L-phenylalanine mustard L-Sarcolysin ; Biological: aldesleukin; Given SC; Other Names: IL-2 Proleukin recombinant human interleukin-2 recombinant interleukin-2 ; Biological: sargramostim; Given SC; Other Names: GM-CSF Leukine Prokine ; Procedure: peripheral blood stem cell transplantation; Undergo autologous peripheral blood stem cell infusion; Other Names: PBPC transplantation PBSC transplantation peripheral blood progenitor cell transplantation transplantation, peripheral blood stem cell ; Radiation: radiation therapy; May undergo radiotherapy after completion of IL-2/GM-CSF; Other Names: irradiation radiotherapy therapy, radiation

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/Puget Sound Oncology Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Leona A Holmberg, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Leona Holmberg, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00003199
• Other Study ID Numbers: PSOC 1605; NCI-2010-00728
• First Posted: Jan 27, 2003
• Last Update Posted: Jul 12, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Inflammatory Breast Neoplasms; Tamoxifen; Aldesleukin; Melphalan; Busulfan; Thiotepa; Interleukin-2; Sargramostim

Study Results

Participant Flow

Arm/Group Title	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
Arm/Group Description	See Detailed Description. tamoxifen citrate: Given orally busulfan: Given orally thiotepa: Given IV melphalan: Given IV aldesleukin: Given SC sargramostim: Given SC peripheral blood stem cell transplantation: Undergo autologous peripheral blood stem cell infusion radiation therapy: May undergo radiotherapy after completion of IL-2/GM-CSF
Period Title: Overall Study
STARTED	50
COMPLETED	28
NOT COMPLETED	22

Baseline Characteristics

Arm/Group Title	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
Arm/Group Description	See Detailed Description. tamoxifen citrate: Given orally busulfan: Given orally thiotepa: Given IV melphalan: Given IV aldesleukin: Given SC sargramostim: Given SC peripheral blood stem cell transplantation: Undergo autologous peripheral blood stem cell infusion radiation therapy: May undergo radiotherapy after completion of IL-2/GM-CSF
Overall Participants	50
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	50 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	50 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	50 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2%
Asian	7 14%
Native Hawaiian or Other Pacific Islander	4 8%
Black or African American	1 2%
White	37 74%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Event-free Survival
Description	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.
Time Frame	11 years

Outcome Measure Data

Analysis Population Description

Study-wide, 20 patients out of 50 have event-free survival.

Arm/Group Title	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
Arm/Group Description	See Detailed Description. tamoxifen citrate: Given orally busulfan: Given orally thiotepa: Given IV melphalan: Given IV aldesleukin: Given SC sargramostim: Given SC peripheral blood stem cell transplantation: Undergo autologous peripheral blood stem cell infusion radiation therapy: May undergo radiotherapy after completion of IL-2/GM-CSF
Measure Participants	50
Stage IIIB Disease	11 22%
Stage IV Disease	9 18%

2. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	11 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
Arm/Group Description	See Detailed Description. tamoxifen citrate: Given orally busulfan: Given orally thiotepa: Given IV melphalan: Given IV aldesleukin: Given SC sargramostim: Given SC peripheral blood stem cell transplantation: Undergo autologous peripheral blood stem cell infusion radiation therapy: May undergo radiotherapy after completion of IL-2/GM-CSF
Measure Participants	50
Count of Participants [Participants]	18 36%

3. Secondary Outcome

Title	Number of Participants With Toxicity of a Combination of Low-dose IL-2 and GM-CSF
Description	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.
Time Frame	16 Weeks

Outcome Measure Data

Analysis Population Description

28 (56%) of 50 patients started IL-2/GM-CSF immunotherapy. Stopping rules were not met for this study.

Arm/Group Title	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
Arm/Group Description	See Detailed Description. tamoxifen citrate: Given orally busulfan: Given orally thiotepa: Given IV melphalan: Given IV aldesleukin: Given SC sargramostim: Given SC peripheral blood stem cell transplantation: Undergo autologous peripheral blood stem cell infusion radiation therapy: May undergo radiotherapy after completion of IL-2/GM-CSF
Measure Participants	28
Count of Participants [Participants]	6 12%

Adverse Events

Time Frame	BUMELTT toxicity assessed day -8 through day 100 using the Bearman Toxicity Criteria, Grades 3 and 4. IL-2/GM-CSF toxicity over 16 weeks will be assessed using the NCI Toxicity Criteria, Grades 3 and 4.
Arm/Group Title	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
Arm/Group Description	See Detailed Description. tamoxifen citrate: Given orally busulfan: Given orally thiotepa: Given IV melphalan: Given IV aldesleukin: Given SC sargramostim: Given SC peripheral blood stem cell transplantation: Undergo autologous peripheral blood stem cell infusion radiation therapy: May undergo radiotherapy after completion of IL-2/GM-CSF
All Cause Mortality
	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
	Affected / at Risk (%)	# Events
Total	32/50 (64%)
Serious Adverse Events
	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
	Affected / at Risk (%)	# Events
Total	2/50 (4%)
Infections and infestations
Prolonged hospitalization for post-transplant complications	1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Emboli	1/50 (2%)
Other (Not Including Serious) Adverse Events
	TX/Maintenance Therapy for Stage IIIB/IV Breast Cancer
	Affected / at Risk (%)	# Events
Total	50/50 (100%)
Blood and lymphatic system disorders
Myelosuppression	50/50 (100%)
Hematologic	6/28 (21.4%)
Infections and infestations
Infections	16/50 (32%)
Infection	3/28 (10.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.