Breast Neoplasms
Conditions
Keywords
Breast Cancer Metastatic
Brief summary
The current study is to evaluate: Overall response rate for the combination of trastuzumab and SU011248 in metastatic or locally recurrent breast cancer; evaluate safety and tolerability of the combination; measure duration of tumor control and survival; assess patient reported outcomes; assess PK in combination with trastuzumab and compare efficacy and safety.
Interventions
DRUGSU011248/Trastuzumab
SU011248 will be administered orally, starting dose of 37.5 mg daily on a continuous regimen. Trastuzumab will be administered weekly (loading dose 4 mg/kg followed by weekly 2mg/kg) or every 3 weeks (loading dose 8 mg/kg followed by 6mg/kg q3w). Study treatment should continue until progression, withdrawal for other reasons, or for up to 18 months following which patients requiring continued access will be offered SU011248 on a separate protocol.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of breast cancer with evidence of 1) unresectable, locally recurrent, or 2) metastatic disease. * HER2 positive disease (3+ by immunohistochemistry \[IHC\] or FISH-positive) * Candidate for treatment with trastuzumab. Prior treatment with trastuzumab and or/ lapatinib in the neoadjuvant, adjuvant or metastatic disease setting is permitted. Treatment with hormone therapy in the adjuvant and/or advanced disease setting is permitted.
Exclusion criteria
* Prior treatment with \>1 regimen of cytotoxic therapy in the advanced disease setting. Adjuvant chemotherapy is permitted * Prior exposure to trastuzumab if the patient had developed severe hypersensitivity reactions. * Prior treatment on a SU11248 clinical trial. * Uncontrolled brain metastases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Confirmed Objective Disease Response | From start of treatment through 18 months | Objective disease response =participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). A CR was defined as the disappearance of all target and non-target lesions. A PR was defined as a \> = 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions associated to a non-progressive disease response for the non target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Benefit | From start of treatment through 18 months | Percent of participants with confirmed CR, PR or stable disease (SD) for at least 24 weeks on study according to RECIST.CR was defined as disappearance of all target and non-target lesions.PR was defined as \>=30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions associated to non-progressive disease response for non target lesions.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference smallest sum of longest dimensions since treatment started. |
| Progression Free Survival (PFS) | From start of treatment through 18 months | Time from first dose of study treatment to first documentation of objective tumor progression, or to death on-study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. PFS was calculated as (first event date minus first dose date +1) divided by 7. |
| Time to Progression (TTP) | From start of treatment through 18 months | Time from first dose of study treatment to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP was calculated as (first event date minus first dose date +1) divided by 7. |
| Overall Survival (OS) | From start of study treatment until death or 2 years from first study treatment | Time from first dose of study treatment to first documentation of death due to any cause. OS was calculated as (date of death minus first dose date +1) divided by 7 \* 4.33. |
| Probability of Survival at One Year | From start of study treatment until death or 2 years from first study treatment | One- year survival probability was estimated using the Kaplan-Meier method. |
| Duration of Response (DR) | From start of treatment through 18 months | Time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of objective tumor progression or death due to any cause. If tumor progression data included more than 1 date, the first date was used. DR was calculated as (the end date for DR minus first CR or PR that was subsequently confirmed +1) divided by 7. |
| EORTC QLQ (BR23) | From start of treatment through 18 months | BR23: consisted of 23 questions which 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. |
| Dose-corrected Trough Plasma Concentrations (Ctrough) of Sunitinib | Predose on Day 1 of Cycle 3 and 5 | Ctrough = the concentration prior to study drug administration. Dose-corrected values were reported, the reference dose was 37.5 mg. |
| Dose-corrected Ctrough of SU-012662 (Sunitinib's Metabolite) | Predose on Day 1 of Cycle 3 and 5 | Ctrough = the concentration prior to study drug administration. Dose-corrected values were reported, the reference dose was 37.5 mg. |
| Dose-corrected Ctrough of Total Drug (Sunitinib + SU-012662) | Predose on Day 1 of Cycle 3 and 5 | Ctrough = the concentration prior to study drug administration. Dose-corrected values were reported, the reference dose was 37.5 mg. |
| EORTC QLQ-C30 | From start of treatment through 18 months | EORTC QLQ-C30 scales consist of 30 questions: functional (physical/role/cognitive/emotional/ social), symptom (fatigue/nausea/vomiting/pain), global health/QOL, cancer symptom (dyspnea/insomnia/appetite loss/constipation/diarrhea). Feelings in past week: response range: not at all to very much, global/QOL range: very poor to excellent. Scales/single-items averaged, score 0 to 100. Higher functional/global=better functioning and symptom=greater degree of symptoms. |
Countries
Belgium, Canada, France, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab + Sunitinib Trastuzumab was administered intravenously (i.v) weekly (loading 4 mg/kg followed by weekly 2 mg/kg) or every 3 weeks (loading 8 mg/kg followed by 6 mg/kg thrice weekly). Sunitinib began with 37.5 mg by oral capsule once daily in a continuous regimen. Treatment was administered in 4-week cycles. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Death | 1 |
| Overall Study | Lack of Efficacy | 44 |
| Overall Study | Other | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Trastuzumab + Sunitinib |
|---|---|
| Age Continuous | 55.1 Years STANDARD_DEVIATION 12.8 |
| EORTC QLQ Breast Cancer Module (BR23) Function Score : Body image (n=46) | 77.2 scores on a scale STANDARD_DEVIATION 25.4 |
| EORTC QLQ Breast Cancer Module (BR23) Function Score: Sexual enjoyment (n=15) | 53.3 scores on a scale STANDARD_DEVIATION 21.1 |
| EORTC QLQ Breast Cancer Module (BR23) Function Score: Sexual function (n=44) | 21.6 scores on a scale STANDARD_DEVIATION 24.5 |
| EORTC QLQ Breast Cancer Module (BR23) Others :Future health perspective (n=48) | 39.6 scores on a scale STANDARD_DEVIATION 32 |
| EORTC QLQ Breast Cancer Module (BR23) Others :Upset of hair loss (n=6) | 50.0 scores on a scale STANDARD_DEVIATION 27.9 |
| EORTC QLQ Breast Cancer Module (BR23) Symptom Score: Arm (n=48) | 23.8 scores on a scale STANDARD_DEVIATION 25.3 |
| EORTC QLQ Breast Cancer Module (BR23) Symptom Score: Breast (n=47) | 25.9 scores on a scale STANDARD_DEVIATION 27.5 |
| EORTC QLQ Breast Cancer Module (BR23) Symptom Score: systemic therapy side effects(n=48) | 17.2 scores on a scale STANDARD_DEVIATION 17.4 |
| EORTC QLQ-C30 Function Score: Cognitive function (n=49) | 82.0 scores on a scale STANDARD_DEVIATION 25.6 |
| EORTC QLQ-C30 Function Score: Emotional function (n=49) | 62.8 scores on a scale STANDARD_DEVIATION 26.4 |
| EORTC QLQ-C30 Function Score: Global health (n=48) | 66.8 scores on a scale STANDARD_DEVIATION 26.8 |
| EORTC QLQ-C30 Function Score: Physical function (n=49) | 79.5 scores on a scale STANDARD_DEVIATION 21.3 |
| EORTC QLQ-C30 Function Score: Role function (n=49) | 76.2 scores on a scale STANDARD_DEVIATION 30 |
| EORTC QLQ-C30 Function Score: Social function (n=49) | 75.5 scores on a scale STANDARD_DEVIATION 29.9 |
| EORTC QLQ-C30 Symptom Score: Constipation (n=48) | 18.1 scores on a scale STANDARD_DEVIATION 32.9 |
| EORTC QLQ-C30 Symptom Score: Diarrhea (n=49) | 6.8 scores on a scale STANDARD_DEVIATION 15.2 |
| EORTC QLQ-C30 Symptom Score: Dyspnea (n=48) | 22.9 scores on a scale STANDARD_DEVIATION 28.5 |
| EORTC QLQ-C30 Symptom Score: Fatigue (n=49) | 35.6 scores on a scale STANDARD_DEVIATION 27.6 |
| EORTC QLQ-C30 Symptom Score: Financial difficulty (n=48) | 15.3 scores on a scale STANDARD_DEVIATION 28.3 |
| EORTC QLQ-C30 Symptom Score: Insomnia (n=49) | 35.4 scores on a scale STANDARD_DEVIATION 31.5 |
| EORTC QLQ-C30 Symptom Score: Loss of appetite (n=49) | 14.3 scores on a scale STANDARD_DEVIATION 28.1 |
| EORTC QLQ-C30 Symptom Score: Nausea/vomiting (n=49) | 7.1 scores on a scale STANDARD_DEVIATION 18 |
| EORTC QLQ-C30 Symptom Score: Pain (n=49) | 38.8 scores on a scale STANDARD_DEVIATION 33.7 |
| Sex: Female, Male Female | 60 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 59 / 60 |
| serious Total, serious adverse events | 25 / 60 |
Outcome results
Primary
Percentage of Participants With Overall Confirmed Objective Disease Response
Objective disease response =participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). A CR was defined as the disappearance of all target and non-target lesions. A PR was defined as a \> = 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions associated to a non-progressive disease response for the non target lesions.
Time frame: From start of treatment through 18 months
Population: The intent-to-treat (ITT) population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Sunitinib | Percentage of Participants With Overall Confirmed Objective Disease Response | 36.8 percentage of participants |
Secondary
Dose-corrected Ctrough of SU-012662 (Sunitinib's Metabolite)
Ctrough = the concentration prior to study drug administration. Dose-corrected values were reported, the reference dose was 37.5 mg.
Time frame: Predose on Day 1 of Cycle 3 and 5
Population: The PK population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib) and collected plasma values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Sunitinib | Dose-corrected Ctrough of SU-012662 (Sunitinib's Metabolite) | Day 1 (Cycle 3) | 26.7 ng/mL | Standard Deviation 14.4 |
| Trastuzumab + Sunitinib | Dose-corrected Ctrough of SU-012662 (Sunitinib's Metabolite) | Day 1 (Cycle 5) | 24.7 ng/mL | Standard Deviation 12.5 |
Secondary
Dose-corrected Ctrough of Total Drug (Sunitinib + SU-012662)
Ctrough = the concentration prior to study drug administration. Dose-corrected values were reported, the reference dose was 37.5 mg.
Time frame: Predose on Day 1 of Cycle 3 and 5
Population: The PK population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib) and collected plasma values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Sunitinib | Dose-corrected Ctrough of Total Drug (Sunitinib + SU-012662) | Day 1 (Cycle 3) | 80.2 ng/mL | Standard Deviation 39.9 |
| Trastuzumab + Sunitinib | Dose-corrected Ctrough of Total Drug (Sunitinib + SU-012662) | Day 1 (Cycle 5) | 79.7 ng/mL | Standard Deviation 36.3 |
Secondary
Dose-corrected Trough Plasma Concentrations (Ctrough) of Sunitinib
Ctrough = the concentration prior to study drug administration. Dose-corrected values were reported, the reference dose was 37.5 mg.
Time frame: Predose on Day 1 of Cycle 3 and 5
Population: The Pharmacokinetic (PK) population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib) and collected plasma values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Sunitinib | Dose-corrected Trough Plasma Concentrations (Ctrough) of Sunitinib | Day 1 (Cycle 3) | 53.5 nanograms (ng)/milliliter (mL) | Standard Deviation 27.6 |
| Trastuzumab + Sunitinib | Dose-corrected Trough Plasma Concentrations (Ctrough) of Sunitinib | Day 1 (Cycle 5) | 55.0 nanograms (ng)/milliliter (mL) | Standard Deviation 24.8 |
Secondary
Duration of Response (DR)
Time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of objective tumor progression or death due to any cause. If tumor progression data included more than 1 date, the first date was used. DR was calculated as (the end date for DR minus first CR or PR that was subsequently confirmed +1) divided by 7.
Time frame: From start of treatment through 18 months
Population: DR was calculated for the subgroup of participants from the ITT set, with a confirmed objective tumor response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Sunitinib | Duration of Response (DR) | 25.6 weeks |
Secondary
EORTC QLQ (BR23)
BR23: consisted of 23 questions which 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.
Time frame: From start of treatment through 18 months
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Symptom Score: systemic therapy side effects(n=27) | 21.7 scores on a scale | Standard Deviation 15.8 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Function Score : Body image (n=27) | 76.4 scores on a scale | Standard Deviation 29.5 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Function Score: Sexual function (n=24) | 14.6 scores on a scale | Standard Deviation 16.5 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Function Score: Sexual enjoyment (n=10) | 33.3 scores on a scale | Standard Deviation 15.7 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Others :Future health perspective (n=27) | 45.7 scores on a scale | Standard Deviation 34.8 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Symptom Score: Breast (n=27) | 19.4 scores on a scale | Standard Deviation 23.6 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Symptom Score: Arm (n=27) | 21.0 scores on a scale | Standard Deviation 23.9 |
| Trastuzumab + Sunitinib | EORTC QLQ (BR23) | Others :Upset of hair loss (n=6) | 44.4 scores on a scale | Standard Deviation 27.2 |
Secondary
EORTC QLQ-C30
EORTC QLQ-C30 scales consist of 30 questions: functional (physical/role/cognitive/emotional/ social), symptom (fatigue/nausea/vomiting/pain), global health/QOL, cancer symptom (dyspnea/insomnia/appetite loss/constipation/diarrhea). Feelings in past week: response range: not at all to very much, global/QOL range: very poor to excellent. Scales/single-items averaged, score 0 to 100. Higher functional/global=better functioning and symptom=greater degree of symptoms.
Time frame: From start of treatment through 18 months
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Function Score: Global health (n=28) | 56.0 scores on a scale | Standard Deviation 21.4 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Function Score: Physical function (n=28) | 75.2 scores on a scale | Standard Deviation 16.8 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Function Score: Role function (n=28) | 60.1 scores on a scale | Standard Deviation 28.8 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Function Score: Cognitive function (n=28) | 84.5 scores on a scale | Standard Deviation 21.7 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Function Score: Emotional function (n=28) | 66.1 scores on a scale | Standard Deviation 27.5 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Function Score: Social function (n=28) | 66.7 scores on a scale | Standard Deviation 28.3 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Fatigue (n=28) | 45.0 scores on a scale | Standard Deviation 25.3 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Pain (n=28) | 36.9 scores on a scale | Standard Deviation 25.8 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Nausea/vomiting (n=28) | 6.5 scores on a scale | Standard Deviation 10.5 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Dyspnea (n=28) | 26.2 scores on a scale | Standard Deviation 30.6 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Loss of appetite (n=28) | 20.2 scores on a scale | Standard Deviation 24.6 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Insomnia (n=28) | 29.8 scores on a scale | Standard Deviation 27.7 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Constipation (n=27) | 14.8 scores on a scale | Standard Deviation 26.7 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Diarrhea (n=27) | 32.1 scores on a scale | Standard Deviation 32.7 |
| Trastuzumab + Sunitinib | EORTC QLQ-C30 | Symptom Score: Financial difficulty (n=28) | 17.9 scores on a scale | Standard Deviation 29.4 |
Secondary
Overall Survival (OS)
Time from first dose of study treatment to first documentation of death due to any cause. OS was calculated as (date of death minus first dose date +1) divided by 7 \* 4.33.
Time frame: From start of study treatment until death or 2 years from first study treatment
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Sunitinib | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants With Clinical Benefit
Percent of participants with confirmed CR, PR or stable disease (SD) for at least 24 weeks on study according to RECIST.CR was defined as disappearance of all target and non-target lesions.PR was defined as \>=30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions associated to non-progressive disease response for non target lesions.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference smallest sum of longest dimensions since treatment started.
Time frame: From start of treatment through 18 months
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Sunitinib | Percentage of Participants With Clinical Benefit | 56.1 Percentage of Participants |
Secondary
Probability of Survival at One Year
One- year survival probability was estimated using the Kaplan-Meier method.
Time frame: From start of study treatment until death or 2 years from first study treatment
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab + Sunitinib | Probability of Survival at One Year | 91.2 percentage of 1-year survival |
Secondary
Progression Free Survival (PFS)
Time from first dose of study treatment to first documentation of objective tumor progression, or to death on-study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. PFS was calculated as (first event date minus first dose date +1) divided by 7.
Time frame: From start of treatment through 18 months
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Sunitinib | Progression Free Survival (PFS) | 28.0 Weeks |
Secondary
Time to Progression (TTP)
Time from first dose of study treatment to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP was calculated as (first event date minus first dose date +1) divided by 7.
Time frame: From start of treatment through 18 months
Population: The ITT population included all enrolled participants who were treated with the combination (trastuzumab and sunitinib).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab + Sunitinib | Time to Progression (TTP) | 26.0 weeks |