Breast Cancer
Conditions
Keywords
recurrent breast cancer, stage IV breast cancer, male breast cancer
Brief summary
RATIONALE: Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and methotrexate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sunitinib together with combination chemotherapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of sunitinib when given together with cyclophosphamide and methotrexate to see how well they work in treating patients with metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * To determine the maximum tolerated dose of the combination of metronomic dose cyclophosphamide and methotrexate with continuous dosing sunitinib malate. (Phase I) * To determine the time to disease progression in patients with metastatic breast cancer treated with metronomic dose chemotherapy with cyclophosphamide and methotrexate combined with continuous dosing of sunitinib malate. (Phase II) Secondary * To determine the response rate in patients receiving this treatment. * To determine the duration of response in patients receiving this treatment. * To determine the toxicity of this regimen in these patients. * To determine the feasibility by assessment of toxicities of this regimen and number of voluntary withdrawals from the study. * To correlate outcome measures with possible surrogate markers including serial measurements of circulating tumor cells and circulating endothelial cells. OUTLINE: This is a dose-escalation study of sunitinib malate. * Phase I: Patients receive oral sunitinib malate once daily. Beginning 14 days later, patients also receive oral cyclophosphamide once daily on days 1-21 and oral methotrexate twice daily on days 1, 2, 8, 9, 15, and 16. Treatment with sunitinib malate, cyclophosphamide, and methotrexate repeats every 21 days\* in the absence of disease progression or unacceptable toxicity. * Phase II: Patients receive sunitinib malate at the maximum tolerated dose determined in phase I and cyclophosphamide and methotrexate as in phase I. NOTE: \*Course 1 includes 2 weeks of sunitinib malate alone followed by sunitinib malate, cyclophosphamide, and methotrexate for 21 days Blood samples are collected periodically for measurement of circulating tumor cells, circulating endothelial cells, and vascular endothelial growth factor (VEGF) levels. After completion of study treatment, patients are followed for 30 days and then every 2 months for 1 year.
Interventions
DRUGcyclophosphamide
DRUGmethotrexate
DRUGsunitinib malate
OTHERlaboratory biomarker analysis
Sponsors
National Cancer Institute (NCI)
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Pathologically confirmed diagnosis of breast cancer with documented progressive disease * Metastatic disease * Measurable disease as defined by RECIST criteria or evaluable disease * Must have received at least one prior chemotherapy regimen for metastatic breast cancer * Patients refusing all other chemotherapy for breast cancer may enroll without prior treatment * Patients with HER2-overexpression disease must have been previously treated with trastuzumab (Herceptin®) * Patients with stable brain metastases are eligible * Hormone receptor status not specified PATIENT CHARACTERISTICS: * Menopausal status not specified * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Life expectancy ≥ 12 weeks * Absolute Neutrophil Count (ANC) ≥ 1,000/mm³ * Platelet count ≥ 100,000/mm³ * Creatinine ≤ 1.5 times upper limit of normal (ULN) * aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases) * Total bilirubin ≤ 1.5 times ULN * Able to take oral medications and maintain hydration * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 6 months after treatment * No severe concurrent illness including, but not limited to, any of the following: * Congestive heart failure * Significant cardiac disease * Uncontrolled hypertension * Must be able to read and speak English PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 2 weeks since prior treatment, including chemotherapy, hormonal therapy, trastuzumab (Herceptin®), or other targeted therapies * Prior bevacizumab allowed if discontinued for any reason other than toxicity * No potent inducers or inhibitors of CYP3A4 enzymes that effect the metabolism of sunitinib malate * No prior sunitinib malate * No other concurrent investigational therapy * No concurrent radiotherapy * Concurrent bisphosphonates allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Sunitinib (Phase I) | 8 weeks | Patients in each cohort were followed for DLT for at least 8 weeks (2 week lead-in with sunitinib and 6 weeks of treatment with sunitinib and metronomic cyclophosphamide and methotrexate) before opening accrual to the next dose level. Dose limiting toxicity (DLT) defined as: 1) ≥ grade 3 anemia that does not resolve with appropriate growth factors afebrile grade 4 neutropenia that does not resolve with growth factor support after ≥ 7 days 2) grade 4 neutropenia associated with fever (1 reading of oral temperature \> 38.5 degrees Celsius or 3 readings of oral temperature \> 38.0 degrees Celsius in a 24 hour period) 3) ≥ grade 3 thrombocytopenia 4) ≥ grade 3 non-hematologic toxicities, except those that can be controlled to grade 2 or less with appropriate treatment. 5\) Inability to resume treatment with any of the study medications within 14 days of stopping due to treatment related toxicity. |
| Patients With Progression-free Survival (PFS) Greater Than or Equal to 12 Weeks (Phase II) | up to 12 weeks after treatment start date | Progression defined as: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), or appearance of any lesion which had disappeared, or clear worsening of any evaluable disease, or appearance of any new lesion/site, or failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | until disease progression, up to 13 months post treatment | Per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. |
| Duration of Response | until disease progression up to 13 months post treatment | Duration of response refers to duration of single partial response observed per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. Progression: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, or clear worsening of any evaluable disease, or appearance of any new lesion/site, or failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer). |
Countries
United States
Participant flow
Pre-assignment details
Phase I patients received escalating doses of sunitinib in a 3x3 design. None of the patients in the phase I study was included in phase II. Phase I patients receiving treatment at the phase II dose were included in the overall efficacy analysis of the phase II study but were not counted toward the enrollment accrual of the phase II study.
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib, Cyclophosphamide, and Methotrexate Phase I patients received escalating doses of sunitinib in a 3x3 design (12.5, 25, 37.5 mg). Phase I and II patients received sunitinib for 2 weeks, followed by the addition of metronomic cyclophosphamide (50mg/day) and methotrexate (2.5mg BID 2 days/week). Phase II patients received 37.5mg sunitinib during the 2-week lead-in period followed by either 37.5mg sunitinib and metronomic CM or 25mg sunitinib and metronomic CM (dose reduction due to a protocol amendment). | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Sunitinib, Cyclophosphamide, and Methotrexate |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 58 years STANDARD_DEVIATION 15 |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 4 | 6 / 7 | 8 / 10 | 11 / 11 |
| serious Total, serious adverse events | 0 / 4 | 0 / 7 | 1 / 10 | 0 / 11 |
Outcome results
Primary
Maximum Tolerated Dose of Sunitinib (Phase I)
Patients in each cohort were followed for DLT for at least 8 weeks (2 week lead-in with sunitinib and 6 weeks of treatment with sunitinib and metronomic cyclophosphamide and methotrexate) before opening accrual to the next dose level. Dose limiting toxicity (DLT) defined as: 1) ≥ grade 3 anemia that does not resolve with appropriate growth factors afebrile grade 4 neutropenia that does not resolve with growth factor support after ≥ 7 days 2) grade 4 neutropenia associated with fever (1 reading of oral temperature \> 38.5 degrees Celsius or 3 readings of oral temperature \> 38.0 degrees Celsius in a 24 hour period) 3) ≥ grade 3 thrombocytopenia 4) ≥ grade 3 non-hematologic toxicities, except those that can be controlled to grade 2 or less with appropriate treatment. 5\) Inability to resume treatment with any of the study medications within 14 days of stopping due to treatment related toxicity.
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib, Cyclophosphamide, and Methotrexate | Maximum Tolerated Dose of Sunitinib (Phase I) | 37.5 mg |
Primary
Patients With Progression-free Survival (PFS) Greater Than or Equal to 12 Weeks (Phase II)
Progression defined as: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), or appearance of any lesion which had disappeared, or clear worsening of any evaluable disease, or appearance of any new lesion/site, or failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer).
Time frame: up to 12 weeks after treatment start date
Population: Patients who received either 25mg or 37.5mg of sunitinib and were not removed from study due to voluntary withdrawal or PD prior to receiving combination sunitinib and metronomic CM chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib, Cyclophosphamide, and Methotrexate | Patients With Progression-free Survival (PFS) Greater Than or Equal to 12 Weeks (Phase II) | 7 participants |
Secondary
Duration of Response
Duration of response refers to duration of single partial response observed per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. Progression: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, or clear worsening of any evaluable disease, or appearance of any new lesion/site, or failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer).
Time frame: until disease progression up to 13 months post treatment
Population: A partial response was only reported for one patient, while a complete response was not recorded for any patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib, Cyclophosphamide, and Methotrexate | Duration of Response | 10.6 weeks |
Secondary
Overall Response Rate
Per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression.
Time frame: until disease progression, up to 13 months post treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib, Cyclophosphamide, and Methotrexate | Overall Response Rate | 1 participants |