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Letrozole Plus Oral Cyclophosphamide Plus/Minus Sorafenib as Primary Systemic Treatment in Breast Cancer Patients

Primary Purpose

Breast Cancer

Status

Unknown status

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

letrozolo+cyclophosphamide

letrozolo+sorafenib+cyclophosphamide

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring neoadjuvant therapy, sorafenib, letrozolo, cyclophosphamide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

1. Women in postmenopausal status
2. Age> 60 or age > 18 and unfit for chemotherapy with commonly employed regimens in breast cancer patients
3. Diagnosis of invasive BC, T>2, N0-N2, M0,
4. Endocrine Responsive disease according to San Gallen criteria
5. ECOG Performance Status of 0 or 2
6. Life expectancy of at least 12 weeks
7. In case of recent surgery, the wound must be completely healed prior to receiving Sorafenib
8. Subjects with at least one uni-dimensional(for RECIST) or bi-dimensional(for WHO) measurable lesion. Lesions must be measured by CT-scan or MRI
9. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
10. Hemoglobin > 9.0 g/dl
11. Absolute neutrophil count (ANC) >1,500/mm3
12. Platelet count 100,000/μl
13. Total bilirubin < 1.5 times the upper limit of normal
14. ALT and AST < 2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement of their cancer)
15. Alkaline phosphatase < 4 x ULN
16. PT-INR/PTT < 1.5 x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.]
17. Serum creatinine < 1.5 x upper limit of normal.

Exclusion Criteria:

1. History of cardiac disease:congestive heart failure >NYHA class 2;active CAD (MI more than 6 mo prior to study entry is allowed); cardiac arrythmias requiring anti-arrythmic therapy( beta blockers or digoxin are permitted) or uncontrolled hypertension.
2. History of HIV infection or chronic hepatitis B or C (This criteria should be modified to allow Hepatitis B or C in protocols looking at HCC patient population).
3. Active clinically serious infections (> grade 2 NCI-CTC version 3.0)
4. Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry)
5. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
6. History of organ allograft The organ allograft may be allowed as protocol specific.
7. Patients with evidence or history of bleeding diathesis
8. Patients undergoing renal dialysis
9. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry

Sites / Locations

Breast Unit Azienda Ospedaliera Istituti Ospitalieri
Azienda Ospedaliera S.Luigi Orbassano

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

letrozolo+cyclophosphamide

letrozolo+sorafenib+cyclophosphamide

Arm Description

Outcomes

Primary Outcome Measures

Progression free survival

Secondary Outcome Measures

Overall survival

Full Information

NCT ID

NCT00954135

First Posted

August 6, 2009

Last Updated

August 6, 2009

Sponsor

University of Turin, Italy

1. Study Identification

Unique Protocol Identification Number

NCT00954135

Brief Title

Letrozole Plus Oral Cyclophosphamide Plus/Minus Sorafenib as Primary Systemic Treatment in Breast Cancer Patients

Official Title

Letrozole Plus Oral Cyclophosphamide Plus/Minus Sorafenib as Primary Systemic Treatment in Post-menopausal, Estrogen Receptor Positive, Breast Cancer Patients

Study Type

Interventional

2. Study Status

Record Verification Date

August 2009

Overall Recruitment Status

Unknown status

Study Start Date

September 2007 (undefined)

Primary Completion Date

June 2010 (Anticipated)

Study Completion Date

December 2010 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

University of Turin, Italy

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Endocrine therapy is the mainstay of systemic treatment in patients with endocrine responsive breast cancer. Aromatase inhibitors are the most active agents in post-menopausal women. Randomized comparisons either in primary/adjuvant setting or in metastatic disease setting have demonstrated the superiority of these drugs over tamoxifen. Primary systemic treatment administered to breast cancer patients is a useful model to identify baseline features able to predict which patients are most likely to benefit from cytotoxic treatment and is a way to study new biological markers in relation to the predictive information they provide. This treatment modality represents therefore the best way to explore new treatment strategies in particular treatment strategies involving target therapies. We have conducted a randomised phase II trial in which the activity of Letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment has been investigated in a patient population of elderly breast cancer patients. The conclusions were that the combination of letrozole with metronomic cyclophosphamide was a very active scheme. In addition this was the first study demonstrating in vivo the antiangiogenic effect of metronomic scheduling. This study suggests that chemotherapy administered on a metronomic schedule, targeting therefore the neo-angiogenesis, could be synergistic with endocrine therapy with aromatase inhibitors. Sorafenib is a multi-kinase inhibitor targeting Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alfa, Flt-3, c-Kit, and p38. There is a strong rationale of combining different anti-angiogenic agents. At the ASCO 2007 meeting the data of a phase I study exploring the toxicity of a combination of sorafenib and bevacizumab have been presented. The results showed an increased toxicity being dose limiting in some patients. To our knowledge there are no data un activity and toxicity of adding sorafenib to metronomic chemotherapy.

Detailed Description

Primary Objective: To compare the activity of the 2 regimens The primary end point will be the clinical complete response rate of each treatment arm among all registered cases (intent to treat analysis). Secondary Objectives: To compare the 2 treatment arms with respect to: Toxicity Progression Free Survival Overall survival Ancillary studies To evaluate before and after treatment a number of markers of hypoxia, neoangiogenesis, apoptosis, EGFR activating pathways.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer

Keywords

neoadjuvant therapy, sorafenib, letrozolo, cyclophosphamide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

190 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

letrozolo+cyclophosphamide

Arm Type

Active Comparator

Arm Title

letrozolo+sorafenib+cyclophosphamide

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

letrozolo+cyclophosphamide

Intervention Description

Letrozole 2,5 mg/daily + metronomic cyclophosphamide 50 mg/daily for 6 months

Intervention Type

Drug

Intervention Name(s)

letrozolo+sorafenib+cyclophosphamide

Intervention Description

Letrozole (2,5 mg/daily) + "metronomic" cyclophosphamide (50 mg/daily) + Sorafenib (400 mg/bid/daily) for 6 months

Primary Outcome Measure Information:

Title

Progression free survival

Time Frame

six years

Secondary Outcome Measure Information:

Title

Overall survival

Time Frame

six years

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1. Women in postmenopausal status 2. Age> 60 or age > 18 and unfit for chemotherapy with commonly employed regimens in breast cancer patients 3. Diagnosis of invasive BC, T>2, N0-N2, M0, 4. Endocrine Responsive disease according to San Gallen criteria 5. ECOG Performance Status of 0 or 2 6. Life expectancy of at least 12 weeks 7. In case of recent surgery, the wound must be completely healed prior to receiving Sorafenib 8. Subjects with at least one uni-dimensional(for RECIST) or bi-dimensional(for WHO) measurable lesion. Lesions must be measured by CT-scan or MRI 9. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening: 10. Hemoglobin > 9.0 g/dl 11. Absolute neutrophil count (ANC) >1,500/mm3 12. Platelet count 100,000/μl 13. Total bilirubin < 1.5 times the upper limit of normal 14. ALT and AST < 2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement of their cancer) 15. Alkaline phosphatase < 4 x ULN 16. PT-INR/PTT < 1.5 x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.] 17. Serum creatinine < 1.5 x upper limit of normal. Exclusion Criteria: 1. History of cardiac disease:congestive heart failure >NYHA class 2;active CAD (MI more than 6 mo prior to study entry is allowed); cardiac arrythmias requiring anti-arrythmic therapy( beta blockers or digoxin are permitted) or uncontrolled hypertension. 2. History of HIV infection or chronic hepatitis B or C (This criteria should be modified to allow Hepatitis B or C in protocols looking at HCC patient population). 3. Active clinically serious infections (> grade 2 NCI-CTC version 3.0) 4. Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry) 5. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics) 6. History of organ allograft The organ allograft may be allowed as protocol specific. 7. Patients with evidence or history of bleeding diathesis 8. Patients undergoing renal dialysis 9. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alfredo Berruti, MD

Organizational Affiliation

Medical Oncology, Department of clinical and biological sciences Univerity of Turin

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Daniele Generali, MD

Organizational Affiliation

Breast Unit Azienda Ospedaliera Istituti Ospitalieri Cremona

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Alberto Bottini, MD

Organizational Affiliation

Breast Unit Azienda Ospedaliera Istituti Ospitalieri Cremona

Official's Role

Study Director

Facility Information:

Facility Name

Breast Unit Azienda Ospedaliera Istituti Ospitalieri

City

Cremona

Country

Italy

Facility Name

Azienda Ospedaliera S.Luigi Orbassano

City

Orbassano

Country

Italy

12. IPD Sharing Statement

Citations:

PubMed Identifier

16877730

Citation

Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol. 2006 Aug 1;24(22):3623-8. doi: 10.1200/JCO.2005.04.5773.

Results Reference

result

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Letrozole Plus Oral Cyclophosphamide Plus/Minus Sorafenib as Primary Systemic Treatment in Breast Cancer Patients

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