HR+/HER2- Advanced Breast Cancer and Endocrine Resistance

Study Overview
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Brief Summary
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This is a randomized, 2-arm, open-label, multicenter, international phase II trial. A total of 196 patients will be included. The study will include patients with metastatic Hormone Receptor positive / Human Epidermal Growth Factor Receptor (HER2) negative breast cancer with progressive disease after endocrine treatment. Patients will be randomized (1:1) between two treatment arms: A. palbociclib + fulvestrant and b. capecitabine.

Official Title
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A Phase 2, International, Multicenter, Open-labeled, Randomized Trial of PAlbociclib and Fulvestrant vs. Standard Oral Capecitabine In Patients With Hormone Receptor (HR)+ / HER2- Advanced Breast Cancer and Documented Endocrine Resistance

Conditions
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Breast Cancer Metastatic

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Fulvestrant
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women 18 years or older. Postmenopausal, defined by at least one of the following criteria: Prior bilateral oophorectomy Age ≥60 Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the postmenopausal range according to the local laboratory reference. Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status. OR Pre/perimenopausal if treated with goserelin that was initiated at least 4 weeks prior to randomization. Locally advanced or metastatic breast cancer deemed not amenable to curative surgery or curative radiation therapy. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Known estrogen-receptor positive and/or progesterone receptor positive breast cancer reported by local laboratory. Known HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. Documented resistance to endocrine therapy (tamoxifen or aromatase inhibitors) defined as: Recurrence while on or within 12 months after the end of adjuvant endocrine treatment OR Progression while on or within 1 month after the end of endocrine treatment for advanced disease Previous chemotherapy for breast cancer including an anthracycline and a taxane (only one line for metastatic disease) is permitted. Radiological or other objective evidence (eg. new skin lesions or new lymph node lesions) of recurrence during or after the most recent systemic therapy for recurrent / metastatic disease prior to randomization. At least one tumor lesion accessible for biopsy that is a non-bone lesion or a predominantly lytic bone lesion, and that measures at least 10 mm in largest diameter. This lesion must not have been treated previously with irradiation (although the area may have been irradiated before the occurrence of the lesion). Patient is interested to participate in the trial, including the obligatory biopsies at a metastatic site/site before the start of study treatment. Clinically and/or radiographically documented measurable disease according to RECIST v1.1 criteria or bone-only disease with at least one predominantly lytic or mixed bone lesion. For measurable disease, at least one site of disease must have largest tumor diameter of at least: 10 mm if measured by CT-scan, ultrasound, or physical exam 20 mm if measured by Chest X-ray 15 mm if suspiciously enlarged lymph node (short axis) see Eisenhauer et al. for more details All radiology studies must be performed within 28 days prior to registration (35 days if negative). Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7 days prior to enrollment: Hematology: Absolute granulocytes > 1.5 x 109/L, Platelets > 100 x 109/L Biochemistry: Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum creatinine ≤ 1.5 x ULN. 14. APTT and INR ≤ 1.5 x ULN or institution accepted values for biopsy within 7 days prior to enrollment. Signed written informed consent provided by the patient. Exclusion Criteria: Previous treatment with a CDK4/6 inhibitor, mTOR or PI3K inhibitor, fulvestrant or capecitabine. Short-term (<28 days) exposure to mTOR or PI3K inhibitor in the (neo)adjuvant setting is allowed. More than one prior chemotherapy lines for metastatic breast cancer. Previous (neo)adjuvant chemotherapy or for radically treated local or regional relapse is allowed in addition to one prior chemotherapy line for metastatic breast cancer Note: A chemotherapy line in advanced disease is an anticancer regimen that contains at least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression and the decision for its discontinuation was taken within 21 days after starting it, then this regimen does not count as a prior line of chemotherapy. Chemotherapy regimens composed of more than one drug are considered as one line of therapy. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash, sclerotic bone etc). CNS metastases unless asymptomatic and adequately controlled with surgery or radiotherapy. Stable CNS disease is defined as CNS metastases or cord compression that have been definitively treated and the patient is clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization. Leptomeningeal carcinomatosis Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening complications in the short term. Concurrent malignancy of any site, except adequately controlled limited basal cell carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in situ of the cervix. Active cardiac disease or a history of cardiac dysfunction including any of the following: History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry History of documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy QTc > 480 msec as measured by Bazett's formula, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes. Uncontrolled hypertension. Patients being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A (including, but not limited, to - see table 6 - Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) continuously for at least 7 days during any time period in the last 2 weeks prior to randomization. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous severe reactions to a fluoropyrimidine. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment with anticoagulants that preclude intramuscular administration of drugs. Ongoing pregnancy or lactation. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. A previous metastatic tumor biopsy reported to be negative for both estrogen receptor and progesterone receptor (i.e. <1% for both), or positive for HER2 status (amplified ERBB2).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib and fulvestrant<br>Combination of palbociclib and fulvestrant Palbociclib: 125 mg capsule administered orally once daily for 21 consecutive days followed by 7 days off treatment. Dose modification is recommended based on individual safety and tolerability. Fulvestrant: 500 mg administered intramuscularly on days 1 and 15 of cycle 1, and then on day 1 of each subsequent 28-day cycle. | Drug: Palbociclib<br>* 75-125 mg capsule orally once daily for 21 consecutive Days followed by 7 Days of treatment.<br>* Other names: Ibrance;Drug: Fulvestrant<br>* 500 mg intramuscularly Days 1 and 15 of cycle 1, and then on Day 1 of each subsequent 28-days cycle.<br>* Other names: Faslodex;|
| Active Comparator: Capecitabine<br>1,000 mg/m2 tablet administered orally twice daily for 2 weeks followed by one week of rest. Depending on adverse reactions, both dose escalation and dose reductions will be performed. | Drug: Capecitabine<br>* Oral tablet 500 - 1,250 mg/m2 twice Daily, for 2 weeks followed by 1 week of rest.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS), as assessed locally by the investigator. | Time to progression will be measured according to the RECIST criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression. | Time from the date of randomization to the date of progression, assessed up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health related quality of life score EuroQol (EQ-5D) | Change from baseline to Health related quality of life score EuroQol (EQ-5D) | Baseline to progression up to 2 years | 
| Health related quality of life score EORTC QLQ-C30 | European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30). | Baseline to progression up to 2 years | 
| Health related quality of life score EORTC QLQ-BR23 | European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23). | Baseline to progression up to 2 years | 
| Correlation of efficacy measures with tumor Biomarkers | PgR IHC status (10% cut-off), will be correlated with PFS | Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years.. | 
| Correlation of efficacy measures with tumor Biomarkers | Ki67 IHC status, will be correlated with PFS | Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. | 
| Correlation of efficacy measures with tumor Biomarkers | ESR1 DNA somatic mutation status, will be correlated with PFS | Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. | 
| Correlation of efficacy measures with tumor Biomarkers | Somatic mutations in cancer genes identified by sequencing, will be correlated with PFS | Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. | 
| Correlation of efficacy measures with tumor Biomarkers | SET index, will be correlated with PFS | Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years. | 
| Overall survival (OS) | Overall survival from time of randomization to death from any cause. | Time from randomization to death from any cause, assessed up to 5 years. | 
| 1-year survival | 1-year survival rate from time of randomization to death from any cause. | Time from randomization to death from any cause, assessed up to 5 years. | 
| 2-year survival | 2-year survival rate from time of randomization to death from any cause. | Time from randomization to death from any cause, assessed up to 5 years. | 
| Objective response | Objective tumor response will be measured according to the RECIST criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression. | From randomization until end of treatment, assessed up to 5 years. | 
| Duration of response | Response duration will be measured from the time measurement criteria for complete response (CR)/ partial response (PR) (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. | From randomization until end of treatment, up to 5 years. | 
| Clinical Benefit Rate | Clinical Benefit Rate is defined as CR+PR+stable disease (SD) for > 24 weeks | From randomization until end of treatment, up to 5 years. | 
| Frequency of adverse events (AE) | Adverse events will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 | From randomization until 28 days after the last dose of study medication, assessed up to 5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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palbociclib, fulvestrant, capecitabine