Breast Cancer, Breast Neoplasm
Conditions
Keywords
Advanced, Breast, Cancer, Hormone Resistance, Pazopanib, anastrozole, arimidex, letrozole, femara
Brief summary
The purpose of this study is to evaluate the clinical benefit rate at 12 weeks from the addition of pazopanib to a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) in patients with hormone receptor positive advanced breast cancer progressing on the same NSAI hormone therapy.
Detailed description
In this trial, the investigators propose to evaluate the role of VEGFR blockade with the tyrosine kinase inhibitor pazopanib in combination with nonsteroidal aromatase inhibitors (NSAI) in patients who are progressing or have relapsed on the same NSAI hormone therapy given for advanced or early stage breast cancer. If this trial demonstrates clinical benefit, this all oral combination could be tested in both the neoadjuvant and metastatic settings in a randomized phase II design. In order to investigate potential factors predicting response or resistance to pazopanib and NSAIs, several translational studies have been incorporated into this trial. The prognostic value of circulating tumor cells (CTC) has been demonstrated in several studies in breast cancer, especially in advanced stage \[35-38\]. At University of California, San Francisco (UCSF) in the laboratory of Dr. John Park, the investigators have demonstrated expertise in the measurement of CTC in patients with advanced stage breast cancer by IC/FC assay. CTC are first enriched with immunomagnetic beads coated with EpCAM, then EpCAM+, CD45-, nucleic acid+ cells are detected by flow cytometry. This technique is highly sensitive and reproducable, and allows sorting of cells for molecular analysis as well as analysis of cell surface markers\[39\]. In this trial, the investigators will collect patient's peripheral blood samples every 4 weeks while on treatment and follow any reduction of CTC. The mechanisms of hormonal resistance includes intrinsic and acquired pathways: decreased ER expression accounts for intrinsic resistance and the increased receptor tyrosine kinase pathway relates to acquired resistance \[40-42\]. The investigators plan to analyze the mutation of PI3K/Akt and deletion of PTEN by sequencing in CTC (depending on numbers of cells, which in turn determines feasibility), in order to make a preliminary assessment of potential markers of response to pazopanib. The tumor microenvironment plays an important role in cancer development and progression. Clinical studies have revealed that the increased T regulatory cells (Treg), high ratios of CD4/CD8 T lymphocytes, and extra follicular B cells in primary tumors correlated with worse overall survival \[43-45\]. Recently, studies from preclinical models have shown that tumor associated macrophages (TAM) can promote pulmonary metastases in breast cancer animal models, and in both the preclinical and clinical settings are associated with worse clinical outcome \[46-48\]. TGFβ has been linked to hormonal resistance in breast cancer. The activation of TGFβ leads to increased regulatory CD4+ T cells and decreased cytotoxic CD8+ T cells in the tumor microenvironment \[49\]. A recent study in non-small cell lung cancer suggests that baseline and post-treatment levels of cytokines, particularly IL-4 and IL-12 correlated with response to pazopanib\[50\]. In this study, the investigators will collect patient's serum to monitor the level of cytokines at baseline and during treatment, the investigators will compare the change of cytokine level with pazopanib in each patient, and also compare between responders and non-responders. This information may help us to identify biomarkers that would predict response to antiangiogenic therapy and to identify possible mechanisms of resistance.
Interventions
DRUGPazopanib
Oral, 800mg tablet daily per cycle
Sponsors
GlaxoSmithKline
Hope Rugo, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects must provide written informed consent prior to performance of study specific procedures or assessments, and must be willing to comply with treatment and follow up. \- Procedures conducted as a part of routine clinical management of the subject (e.g., blood count, imaging study) and obtained prior to signed informed consent may be utilized for Screening or Baseline purposes provided these tests are obtained as specified in the protocol). 2. Subjects must have measurable or evaluable disease. Disease sites that are evaluable for progression but not measurable per RECIST guidelines include: * Bone lesions * Previously irradiated lesions * Cutaneous manifestations (non-discreet lesions only) 3. Age ≥ 18 years. 4. Postmenopausal women defined by one of the criteria: * No spontaneous menses for at least 12 months if the subject is ≥ 50 years old; * Amenorrheic for at least 12 months if the subject is \< 50 years old, with serum estradiol within the institutional postmenopausal range; * Bilateral oophorectomy; * If prior hysterectomy but intact ovaries, must be ≥ 55 years old, or have serum estradiol within the postmenopausal range; * If premenopausal, must be on a GnRH agonist (leuprolide or goserelin) with serum estradiol levels within the institutional postmenopausal range. 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. 6. Histologically or cytologically confirmed estrogen receptor (ER) and/or progesterone receptor (PgR) positive carcinoma of the breast with unresectable, locally advanced and/or metastatic (AJCC Stage IV) disease. 7. Subjects must have received prior hormonal therapy for the treatment of breast cancer as follows: * Progression must be documented while taking a nonsteroidal aromatase inhibitor including anastrozole or letrozole. * No more than 2 prior hormonal therapies for metastatic disease. * If hormonal therapy was administered in the adjuvant setting, subjects must have received therapy for at least 6 months prior to developing metastatic disease. Note: A regimen of sequential tamoxifen/AI in the adjuvant setting is considered to be one therapy \- If hormonal therapy was administered in the metastatic setting, subjects must have received therapy for at least 3 months prior to progression 8. Subjects whose tumors overexpress ErbB2 are eligible provided that they have progressed following therapy which included trastuzumab and/or lapatinib. Note for prior lapatinib: Subjects must have completed therapy with lapatinib at least 7 days prior to the first dose of study drug. Note for prior trastuzumab: Subjects who received Q3 weekly, Q2 weekly or Q1 weekly must have completed therapy with trastuzumab at least 3 weeks, 2 weeks or 1 week, respectively, prior to the first dose of study drug. 9. Adequate hematologic and hepatic function as defined in Protocol Table 1 10. Subjects must have discontinued hormone replacement therapy (HRT) (e.g., conjugated estrogens tablets, USP or premarin), at least 28 days prior to receiving the first dose of randomized therapy. 11. Radiotherapy prior to initiation of therapy is allowed to a limited area (e.g., palliative treatment for painful bone metastases), if it is not the sole site of disease. Subjects must have completed treatment at least one week prior to starting study drugs, and must have recovered from all treatment-related toxicities. 12. Bisphosphonate or RANK ligand inhibitor therapy for bone metastases is allowed. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted; 13. Ability to swallow and retain oral medication.
Exclusion criteria
1. Prior use of pazopanib 2. Premenopausal levels of estradiol, or ongoing menses (see definitions of menopause above). 3. Known central nervous system (CNS) metastases or leptomeningeal carcinomatosis. Screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if the subject has clinical findings suggestive of CNS metastasis. 4. History of another active malignancy. Note: Subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. 5. Clinically significant gastrointestinal abnormalities which might interfere with oral dosing, including, but not limited to: * Malabsorption syndrome * Major resection of the stomach or small bowel that could affect the absorption of study drug * Inflammatory bowel disease * Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation * History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment 6. Presence of uncontrolled infection. 7. Prolongation of corrected QT interval (QTc) \>480msecs. 8. History of any one or more of the following cardiovascular conditions within the past 6 months: * Angioplasty or stenting * Myocardial infarction * Unstable angina * Coronary artery by-pass graft surgery * Symptomatic peripheral vascular disease 9. Class II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA). 10. Use of an investigational agent, including an investigational anti-cancer agent, within 14 days prior to the first dose of study drug. 11. Prior use of an investigational drug that targets VEGF or VEGF receptors. 12. Any ongoing toxicity from prior anti-cancer therapy that is \> Grade 1 and/or that is progressing in severity. 13. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥140mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg). Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Blood pressure must be re-assessed prior to start of study therapy. The mean SBP/DBP values must be \<140/90mmHg (OR 150/90mmHg, if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study. 14. History of cerebrovascular accident (CVA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulant agents for at least 6 weeks are eligible. 15. Major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer not related to cancer (procedures such as catheter placement not considered to be major). 16. Evidence of active bleeding or bleeding diathesis. 17. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Benefit (CB) | 12 weeks | For the purpose of this study, participants who obtained a complete response (CR), partial response (PR), or stable disease (SD) at 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 were defined as having a clinical benefit from the treatment. An overall response rate of 20% was considered to be clinically meaningful. All participants who take at least two weeks of study drug and the non-steroidal aromatase inhibitor were evaluated for toxicity and efficacy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | up to 2 years | Evaluate progression free survival with ongoing evaluations at 12 week intervals until progression or up to 2 years, whichever is first. |
| Number of Participants Experiencing Any Treatment-related Adverse Events (AE) | up to 2 years | All patients who take at least two weeks of study drug and the non-steroidal aromatase inhibitor will be evaluable for treatment-related toxicity by ongoing evaluations at 4 week intervals until progression or up to 2 years, whichever is first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib in Combination With a NSAI Non-randomized, open label
Pazopanib: Oral, 800mg tablet daily per cycle | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Pazopanib in Combination With a NSAI |
|---|---|
| Age, Customized 40-49 years | 4 Participants |
| Age, Customized 50-59 years | 13 Participants |
| Age, Customized 60-69 years | 9 Participants |
| Age, Customized 70-79 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 30 |
| other Total, other adverse events | 27 / 30 |
| serious Total, serious adverse events | 8 / 30 |
Outcome results
Primary
Number of Participants With Clinical Benefit (CB)
For the purpose of this study, participants who obtained a complete response (CR), partial response (PR), or stable disease (SD) at 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 were defined as having a clinical benefit from the treatment. An overall response rate of 20% was considered to be clinically meaningful. All participants who take at least two weeks of study drug and the non-steroidal aromatase inhibitor were evaluated for toxicity and efficacy
Time frame: 12 weeks
Population: Twenty-eight patients met the 2 weeks of treatment minimum needed to be considered evaluable for this endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pazopanib in Combination With a NSAI | Number of Participants With Clinical Benefit (CB) | 13 Participants |
Secondary
Number of Participants Experiencing Any Treatment-related Adverse Events (AE)
All patients who take at least two weeks of study drug and the non-steroidal aromatase inhibitor will be evaluable for treatment-related toxicity by ongoing evaluations at 4 week intervals until progression or up to 2 years, whichever is first.
Time frame: up to 2 years
Population: Twenty-eight patients met the 2 weeks of treatment minimum needed to be considered evaluable for this endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pazopanib in Combination With a NSAI | Number of Participants Experiencing Any Treatment-related Adverse Events (AE) | 26 Participants |
Secondary
Progression Free Survival
Evaluate progression free survival with ongoing evaluations at 12 week intervals until progression or up to 2 years, whichever is first.
Time frame: up to 2 years
Population: Twenty-eight patients met the 2 weeks of treatment minimum needed to be considered evaluable for this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib in Combination With a NSAI | Progression Free Survival | 20 weeks |