Study Of SU011248 Versus Chemotherapy For Patients With Previously Treated Triple Receptor Negative Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to compare progression free survival for SU011248 [sutent (sunitinib malate)] versus standard of care therapy in patients with previously treated, advanced, triple receptor negative (ER, PR, HER2) locally recurrent or metastatic breast cancer.

Official Title
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A Randomized Phase 2 Study Of SU011248 Versus Standard-Of-Care For Patients With Previously Treated, Advanced, Triple Receptor Negative (ER, PR, HER2) Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: SU011248
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recurrent or metastatic breast cancer Estrogen receptor (ER), progestin receptor (PR) and HER2/neu receptor (HER2) negative status Prior treatment with an anthracycline and a taxane in the adjuvant or advanced disease setting Relapse following adjuvant chemotherapy within 6 months of last treatment and/or received one or two chemotherapy regimens for advanced disease Exclusion Criteria: More than two chemotherapy regimens for advanced disease Uncontrolled/symptomatic spread of cancer to the brain

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: SU011248<br>* SU011248 capsules administered orally, daily in a continuous regimen, 3-week cycles, starting dose of 37.5 mg daily. 1-week treatment rests and dose reductions allowed for dose-limiting toxicity. Dose escalate SU011248 to 50-mg daily if minimal toxicities . Study will continue until disease progression. Patients randomized to or crossed over to SU011248 may continue beyond the time of Response Evaluation Criterion in Solid Tumors (RECIST) -defined progression at the discretion of the investigator in the case of clinical benefit.<br>* Other names: Sutent, sunitinib malate;|
| Active Comparator: B<br> | Drug: Chemotherapy<br>* The choice of chemotherapy will be at the discretion of the investigator within the limits outlined below. Capecitabine - 1000-1250 mg/m2 twice daily days 1-14 every 3 weeks Vinorelbine - 25-30 mg/m2 rapid intravenous infusion or 60-80 mg/m2 oral weekly, expressed in 3-week cycles Docetaxel - 75-100 mg/m2 every 3 weeks Paclitaxel - 175-200 mg/m2 every 3 weeks Paclitaxel - 80-90 mg/m2 weekly, in a continuous regimen expressed in 3-week cycles or administration of 3 weeks of treatment followed by 1 week of rest. Use of the 3/1 regimen will require extra care in scheduling disease assessments. Gemcitabine - 800-1250 mg/m2 Days 1 and 8 every 3 weeks Study will continue until disease progression or it is in the best interest of the patient to discontinue based on achievement of maximum benefit or tolerability issues. At the time of progression patients randomized to chemotherapy will be offered crossover to single agent SU011248.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Time in months from start of study treatment to first documentation of objective tumor progression (per RECIST) or death due to any cause. PFS was calculated as (first event date minus first randomization date plus 1) divided by 30.4. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was Death). | Baseline, every 6 weeks until disease progression or death (up to 3 years from first dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Objective Response | Objective response based assessment of confirmed response (CR) or confirmed partial response (PR) according to RECIST. CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those with a greater than or equal to (≥) 30% decrease in the sum of the longest dimensions (SLD) of the target lesions taking as a reference the baseline SLD. | Baseline until response or disease progression (up to 3 years from first dose) | 
| Duration of Response (DR) | Time in months from the first documentation of objective tumor response (CR or PR) to objective tumor progression or death. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 30.4. DR was calculated for the subgroup of participants with a confirmed objective tumor response. | Time from first response to disease progression up to 3 years from first dose | 
| Survival Probability at 1 Year | Probability that the participants will survive at end of 1 year from the first dose of study treatment. Calculated using data collected from baseline until death (up to 3 years after first dose of study medication). Probability calculated from Kaplan-Meier estimate. | Baseline until death (up to 3 years after first dose of study medication) | 
| Overall Survival (OS) | Time in months from the date of randomization to date of death due to any cause. OS was calculated as (date of death minus randomization date plus 1) divided by 30.4. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death). | Baseline until death (up to 3 years after first dose of study medication) | 
| Health Related Quality of Life (HRQoL) and Disease Related Symptoms as Measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire (EORTC-QLQ-C30) | EORTC QLQ-C30: global health/QoL, functional domains (physical, role, cognitive, emotional, social), and symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea). Recall period: past week; response range: not at all to very much; global/QoL range: very poor to excellent. Scale score range: 0 to 100. Higher functional/global QoL score = better functioning and higher symptom score = greater degree of symptoms. | Day 1, Cycle 1; Day 1, odd number cycles; and end of treatment (EOT)/withdrawal | 
| HRQoL and Disease Related Symptoms as Measured by EORTC-QLQ-C30 Breast Cancer Module (BR23) Score | BR23: measured disease related symptoms of dry mouth, eye pain, hair loss, hot flushes, attractiveness, future health, sexual activity, arm/shoulder pain, breast pain, swollen breast, and skin problems on the breast. Recall period: past week; response range: not at all to very much. Scale score range: 0 to 100. Higher symptom score = greater degree of symptoms. | Day 1, Cycle 1; Day 1, odd number cycles; and EOT/withdrawal | 
| Observed Plasma Trough Concentrations (Ctrough) of Sunitinib |  | Predose Day 1, Cycles 1, 2, 3, 4, 5 and 7 and Day 15 of Cycles 1, 2, and 3 | 
| Ctrough of SU012662 (Metabolite of Sunitinib) |  | Predose Day 1, Cycles 1, 2, 3, 4, 5 and 7 and Day 15 of Cycles 1, 2, and 3 | 
| Ctrough of Total Drug (Sunitinib + SU012662) |  | Predose Day 1, Cycles 1, 2, 3, 4, 5 and 7 and Day 15 of Cycles 1, 2, and 3 | 
| Dose-corrected Ctrough of Sunitinib | Ctrough = plasma concentration of sunitinib prior to study drug administration, dose corrected using the following formula Intended Dose/Actual Dose, where Actual Dose: the dose the participant received over the last 10 consecutive days and Intended Dose: the starting dose per study protocol. | Predose Day 1, Cycles 1, 2, 3, 4, 5 and 7 and Day 15 of Cycles 1, 2, and 3 | 
| Dose-corrected Ctrough of SU012662 (Metabolite of Sunitinib) | Ctrough = plasma concentration of SU012662 prior to study drug administration, dose corrected using the following formula Intended Dose/Actual Dose, where Actual Dose: the dose the participant received over the last 10 consecutive days and Intended Dose: the starting dose per study protocol. | Predose Day 1, Cycles 1, 2, 3, 4, 5 and 7 and Day 15 of Cycles 1, 2, and 3 | 
| Dose-corrected Ctrough of Total Drug (Sunitinib + SU012662) | Ctrough = plasma concentration of total drug (Sunitinib + SU012662) prior to study drug administration dose corrected using the following formula Intended Dose/Actual Dose, where Actual Dose: the dose the participant received over the last 10 consecutive days and Intended Dose: the starting dose per study protocol. | Predose Day 1, Cycles 1, 2, 3, 4, 5 and 7 and Day 15 of Cycles 1, 2, and 3 | 
| Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) | Plasma concentrations of sVEGFR2 were examined as a potential pharmacodynamic marker | Baseline (Cycle 1, Day 1), Day 1 (Cycles 2, 3, 4, 5, and 7), and EOT/withdrawal | 
| Plasma Concentration of Soluble Vascular Endothelial Growth Factor Receptor 3 (sVEGFR3) | Plasma concentrations of sVEGFR3 were examined as a potential pharmacodynamic marker | Baseline (Cycle 1, Day 1), Day 1 (Cycles 2, 3, 4, 5, and 7), and EOT/withdrawal | 
| Plasma Concentration of Soluble Vascular Endothelial Growth Factor A (sVEGF-A) | Plasma concentrations of sVEGF-A were examined as a potential pharmacodynamic marker | Baseline (Cycle 1, Day 1), Day 1 (Cycles 2, 3, 4, 5, and 7), and EOT/withdrawal | 
| Plasma Concentration of Soluble Placental Growth Factor (sPlGF) | Plasma concentrations of sPlGF were examined as a potential pharmacodynamic marker | Baseline (Cycle 1, Day 1), Day 1 (Cycles 2, 3, 4, 5 and 7), and EOT/withdrawal | 
| Plasma Concentration of Soluble Kinase Insert Domain for Tyrosine (sKIT), a Stem Cell Factor Receptor | Plasma concentrations of sKIT were examined as a potential pharmacodynamic marker | Baseline (Cycle 1, Day 1), Day 1 (Cycles 2, 3, 4, 5 and 7), and EOT/withdrawal | 
| Circulating Endothelial Cells (CEC) | Blood samples were collected to enumerate the number of total CECs and sVEGFR1, sVEGFR2 and sVEGFR3 protein expression and/or cellular viability. | Days 1 and 15 of Cycles 1, 2 and 3, Day 1 of Cycles 4 and 5, and every odd cycle thereafter, and EOT/withdrawal | 
| Circulating Tumor Cells (CTC) | Blood samples were collected to enumerate the number of total CTCs and insulin growth factor 1R positive (IGF-1R+) CTCs | Days 1 and 15 of Cycles 1, 2 and 3, Day 1 of Cycles 4 and 5, and every odd cycle thereafter, and EOT/withdrawal |