Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Hormones

Fulvestrant

Estrogens

Endothelial Growth Factors

Mitogens

Estrogen Receptor Modulators

Aromatase Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Antineoplastic Agents, Hormonal

Hormone Antagonists

Tyrosine

Fulvestrant 500mg Intra Muscular (IM) Day 1 (D1), D15, then D1 of every 28 day cycle Vandetanib 300 mg Per os (po) daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. Computerised Axial Tomography (CT) at week 8, 16, 24 then 12 weekly.

Fulvestrant 500mg IM D1, D15, then D1 of every 28 day cycle Placebo po daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. CT at week 8, 16, 24 then 12 weekly.

The pharmacology and mode of action studies established that fulvestrant is the first agent in a new class of anti-estrogens that down-regulate the estrogen receptor (ER), and can therefore be described as an ER down-regulator.

Vandetanib is a potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR; also known as kinase insert domain containing receptor)-2, an endothelial cell receptor for vascular endothelial growth factor (VEGF), and also possesses activity against epidermal growth factor receptor (EGFR) and Rearranged during Transfection (RET) tyrosine kinases.

Vandetanib

Joanna Smith, BSc MSc PhD

Tracie Madden, PhD

Tamas Hickish, MA MD FRCP

Anne Hong, MB ChB MRCP

Duncan Wheatley, MBBS, FRCR

Robert Jones, MD PhD MCRCP

Mark Beresford, MD MRCP FRCR

A randomised double blind placebo controlled phase II study of fulvestrant with or without the addition of vandetanib as treatment for patients with metastatic breast cancer resistant to aromatase inhibitor therapy.

For patients with advanced breast cancer that has spread around the body, hormone therapy is often the best treatment. As well as being very effective, this means that patients do not experience the toxicity and inconvenience of chemotherapy. However, eventually the cancer is likely to become resistant to hormone therapy and in this situation, although other hormone drugs can be used, they sometimes do not work very well. So it is important to find ways of getting the cancer to respond to hormone treatment again.

There are many different ways in which breast cancer cells become resistant to hormone treatments, including a 'signalling' pathway in the cells called RET \[Receptor tyrosine kinase RET\] REarranged during Transfection. Research has shown increased activity of RET signalling pathways in hormone resistant cancer cells.

Vandetanib is an oral drug that inhibits RET signalling in cells and has been shown in laboratory studies to prevent the growth of breast cancer cells which have become resistant to hormone therapy. Hormone therapy drugs include tamoxifen, and the aromatase inhibitors (anastrozole, letrozole and exemestane). The investigators therefore believe that giving vandetanib together with hormone therapy may help prevent resistance to treatment in patients with breast cancer. In this trial the investigators will combine this drug with fulvestrant, another hormone therapy drug which is sometimes used alone in patients who have developed resistance to aromatase inhibitors, or tamoxifen. So patients entering the trial will have one drug, fulvestrant, which is known to work and may also be given the experimental drug, vandetanib.

To properly determine if vandetanib works as the investigators believe, this study will compare the activity of vandetanib combined with fulvestrant with fulvestrant combined with an inactive, 'placebo' tablet in a group of patients for whom treatment with single agent fulvestrant is thought appropriate. The investigators plan to recruit a total of 160 patients. Half of them will be given fulvestrant and vandetanib and half will be given fulvestrant and placebo, and the treatment a particular patient will get will be chosen by random chance. Neither the patient nor the patients doctor will know whether the patient is getting vandetanib or the inactive placebo. The most important measure of effect will be the time until the cancer grows again, but the study will also look closely at the side effects of the drugs. The investigators will also look at whether the way in which an individual responds relates to the results from laboratory studies on the RET pathways carried out on previously stored tumour samples. This will mean that patients will not need to have additional biopsy samples taken.

Fulvestrant +/- Vandetanib in Advanced Aromatase Inhibitor Resistant Breast Cancer

A Randomised Double Blind Placebo Controlled Phase II Study of Fulvestrant With or Without the Addition of Vandetanib as Treatment for Patients With Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy

Time to event based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. - Time from randomisation to any disease progression and/or death.

Objective Response Rate as assessed by the Response Evaluation Criteria in Solid Tumours (RECIST). Disease progression will be formally assessed according to the RECIST v1.1 criteria.

Time from enrolment to death from any cause with those still alive censored at date last seen.

The influence of RET signalling pathway components expression on vandetanib activity.

This outcome will observe the number of side effects of the combined vandetanib and fulvestrant drug regime as recorded via real-time serious adverse event reporting.

This outcome will assess the number of patients requiring dose delays, reductions, and/or study withdrawal to manage side effects recorded via real-time serious adverse event reporting.

The clinical benefit rate will be assessed by measuring the proportion of patients with no disease progression after six months of treatment. Disease progression will be formally assessed according to the RECIST v1.1 criteria.

Cancer Research UK

AstraZeneca

Velindre NHS Trust

Senior Trial Manager

Breast Diseases

Skin Diseases

Letrozole

Anastrozole

Pazopanib

Hope Rugo, M.D.

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.

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.

Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib

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

Evaluate progression free survival with ongoing evaluations at 12 week intervals until progression or up to 2 years, whichever is first.

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.

GlaxoSmithKline

Hope Rugo, MD

Clinical Professor

Non-randomized, open label

Pazopanib: Oral, 800mg tablet daily per cycle

Pazopanib in Combination With a NSAI

40-49 years

50-59 years

60-69 years

70-79 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Hope Rugo, MD

Twenty-eight patients met the 2 weeks of treatment minimum needed to be considered evaluable for this endpoint.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Fulvestrant +/- Vandetanib in Advanced Aromatase Inhibitor Resistant Breast Cancer	NCT02530411	Neoplasms	Fulvestrant Vandetanib	18 Years -	Velindre NHS Trust
Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib	NCT01466972	Breast Cancer Breast Neoplasm	Pazopanib	18 Years -	University of California, San Francisco
Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib	NCT01466972	Breast Cancer Breast Neoplasm	Pazopanib	18 Years -	University of California, San Francisco
Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib	NCT01466972	Breast Cancer Breast Neoplasm	Pazopanib	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for hormone resistance