Breast CancerPhase 2NCT01466972
Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib
A Phase 2 study testing Pazopanib in people with Breast Cancer and Breast Neoplasm, run by Hope Rugo, MD at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer, Breast Neoplasm
- What is being tested?
- Pazopanib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Apr 2012to 2 Oct 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
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- 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;
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
- 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.
- 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
- 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.
- Adequate hematologic and hepatic function as defined in Protocol Table 1
- 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.
- 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.
- 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;
- Ability to swallow and retain oral medication.
Who cannot join
- 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
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- 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
- Presence of uncontrolled infection.
- Prolongation of corrected QT interval (QTc) >480msecs.
- 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
- Class II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
- Use of an investigational agent, including an investigational anti-cancer agent, within 14 days prior to the first dose of study drug.
- Prior use of an investigational drug that targets VEGF or VEGF receptors.
- Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity.
- 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.
- 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.
- 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).
- Evidence of active bleeding or bleeding diathesis.
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94143
About this study
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.
Read the 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.
- Conditions
- Breast Cancer, Breast Neoplasm
- Being tested
- Pazopanib
- Keywords
- Advanced, Breast, Cancer, Hormone Resistance, Pazopanib, anastrozole, arimidex, letrozole, femara
- Medical subject headings
- Breast Neoplasms, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PazopanibDrug
Also called Votrient
Oral, 800mg tablet daily per cycle
| Study group | Role | What they receive |
|---|---|---|
| Pazopanib in combination with a NSAI | Experimental | Non-randomized, open label Receives: Drug: Pazopanib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 12 weeks
Secondary outcomes (2)
Progression Free Survival
Evaluate progression free survival with ongoing evaluations at 12 week intervals until progression or up to 2 years, whichever is first.
Measured: up to 2 years
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.
Measured: up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Nov 2011 (estimated)
- Study start27 Apr 2012
- Primary completion7 Dec 2015
- Study completion2 Oct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hope Rugo, MD
- Sponsor type
- University, hospital or other
- Collaborators
- GlaxoSmithKline
- Responsible party
- Sponsor-investigator, Hope Rugo, MD, University of California, San Francisco
- Investigators
- Hope Rugo, M.D., Study chair, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01466972
- Sponsor's protocol ID
- 117513
- Other IDs
- NCI-2012-00494
- Status last verified
- Jul 2020
- First submitted
- 25 Oct 2011
- Last updated
- 8 Jul 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib
- ClinicalTrials.gov ID
- NCT01466972
- Acronym / sponsor ID
- 117513
- Conditions
- Breast Cancer, Breast Neoplasm
- Keywords
- Advanced, Breast, Cancer, Hormone Resistance, Pazopanib, anastrozole, arimidex, letrozole
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Hope Rugo, MDUniversity, hospital or other
- Collaborators
- GlaxoSmithKline
- Study start
- 27 Apr 2012 (actual)
- Primary completion
- 7 Dec 2015 (actual)
- Study completion
- 2 Oct 2019 (actual)
- First posted
- 8 Nov 2011 (estimated)
- Results
- Posted 16 Jun 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pazopanib in combination with a NSAI | Experimental | Drug: PazopanibNon-randomized, open label |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (29 listed)
- 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.
- Subjects must have measurable or evaluable disease. Disease sites that are evaluable for progression but not measurable per RECIST guidelines include:
- Age ≥ 18 years.
- Postmenopausal women defined by one of the criteria:
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
Key exclusion criteria (29 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PazopanibAlso: VotrientOral, 800mg tablet daily per cycle | Drug | Pazopanib in combination with a NSAI |
Primary outcome
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
2 secondary outcomes
Progression Free Survival
Time frame: up to 2 years
Number of Participants Experiencing Any Treatment-related Adverse Events (AE)
Time frame: up to 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jul 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hope Rugo, M.D. study chair
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pazopanib in people with Breast Cancer and Breast Neoplasm, run by Hope Rugo, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 29 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Clinical Benefit (CB) (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jul 2020.