Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib
Overview
- Phase
- Phase 2
- Intervention
- Pazopanib
- Conditions
- Breast Cancer
- Sponsor
- Hope Rugo, MD
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Number of Participants With Clinical Benefit (CB)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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.
Investigators
Hope Rugo, MD
Clinical Professor
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •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).
- •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)
- •Age ≥ 18 years.
- •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;
Exclusion Criteria
- •Prior use of pazopanib
- •Premenopausal levels of estradiol, or ongoing menses (see definitions of menopause above).
- •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.
- •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.
- •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
Arms & Interventions
Pazopanib in combination with a NSAI
Non-randomized, open label
Intervention: Pazopanib
Outcomes
Primary Outcomes
Number of Participants With Clinical Benefit (CB)
Time Frame: 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 Outcomes
- Number of Participants Experiencing Any Treatment-related Adverse Events (AE)(up to 2 years)
- Progression Free Survival(up to 2 years)