| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| In this study we are aiming to investigate how well the combination of palbociclib with the hormone therapy fulvestrant works, compared to standard chemotherapy (capecitabine) alone, in women with metastatic breast cancer (MBC). We are also comparing side effects of these treatments. |
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| E.2.2 | Secondary objectives of the trial |
The study is being carried out to investigate factors in tumour tissue and blood to further our understanding of breast cancer and to see if these can help in deciding at an earlier stage the best treatment for individual patients in the future.
In addition to comparing how effective new treatments are it is also important to examine how they affect patients’ wellbeing. To do this researchers design questionnaires to ask patients about how they are feeling and about what side effects they are having from their cancer and the treatment. These are called Quality of Life questionnaires and this will also be examined in this study.
The safety of the drugs will be assessed by comparing all of the side effects experienced by patients on each of the two treatment arms.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational and Health- Related Quality of Life sub-studies which are integral to the main research protocol.
These are related to the Secondary objectives of the study:
To compare Patient Reported Outcome (PRO) measures in the context of palbociclib + fulvestrant versus capecitabine.
To identify predictive markers of benefit from palbociclib + fulvestrant in endocrine resistant HR+/HER2- advanced breast cancer.
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| E.3 | Principal inclusion criteria |
1. Women 18 years or older.
2. Postmenopausal, defined by at least one of the following criteria:
a. Prior bilateral oophorectomy
b. Age ≥60
c. Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and Follicle Stimulating Hormone (FSH) and oestradiol 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 randomisation.
3. Locally advanced or metastatic breast cancer deemed not amenable to curative surgery or curative radiation therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Known oestrogen receptor-positive and/or progesterone receptor-positive breast cancer reported by local laboratory.
6. 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.
7. Documented resistance to endocrine therapy (tamoxifen or aromatase inhibitors) defined as:
a. Recurrence while on or within 12 months after the end of adjuvant endocrine treatment
OR
b. Progression while on or within 1 month after the end of endocrine treatment for advanced disease
8. Previous chemotherapy for breast cancer including an anthracycline and a taxane (only one line for metastatic disease) is permitted.
9. 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 randomisation.
10. At least one tumour 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).
11. Patient is interested to participate in the trial, including the obligatory biopsies at a metastatic site before the start of study treatment.
12. 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 tumour diameter of at least:
a) 10 mm if measured by CT-scan, ultrasound, or physical exam
b) 20 mm if measured by Chest X-ray
c) 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).
13. Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7 days prior to enrollment:
a. Hematology: Absolute granulocytes > 1.5 x 109/L, Platelets > 100 x 109/L
b. 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.
15. Signed written informed consent provided by the patient. |
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| E.4 | Principal exclusion criteria |
1. 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.
2. 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.
3. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash, sclerotic bone etc).
4. Central Nervous System (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 randomisation.
5. Leptomeningeal carcinomatosis
6. Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening complications in the short term.
7. 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.
8. Active cardiac disease or a history of cardiac dysfunction including any of the following:
a. History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry
b. History of documented congestive heart failure
(New York Heart Association functional classification III-IV)
c. Documented cardiomyopathy
d. 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.
e. Uncontrolled hypertension.
9. Patients being treated with drugs recognised 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 randomisation.
10. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous severe reactions to a fluoropyrimidine.
11. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment with anticoagulants that preclude intramuscular administration of drugs.
12. Ongoing pregnancy or lactation.
13. 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.
14. A previous metastatic tumour biopsy reported to be negative for both oestrogen receptor and progesterone receptor (i.e. <1% for both), or positive for HER2 status (amplified ERBB2). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The comparison of progression free survival between the cohort receiving palbociclib plus fulvestrant, versus those receiving capecitabine, as assessed locally by the Principal Investigator. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CT or MRI scan chest & abdomen to assess cancer- Before starting study treatment and
every 12 weeks for the first 48 weeks and then every 16 weeks up to the end of study treatment.
Research blood sample collection; blood will be taken to examine DNA and proteins and changes in DNA- Before starting study treatment (42 ml taken), End of cycle 1 (37 ml taken day 28 group 1, day 21 group 2, End of treatment (37 ml taken).
Tissue biopsy; to assess whether properties of the tumour have changed- Before starting study treatment,then (Optional) sample at End of cycle 1 (day 28 group 1, day 21 group 2) and end of treatment.
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| E.5.2 | Secondary end point(s) |
Key secondary endpoints
1. PRO endpoints including health related quality of life scores [EuroQol (EQ-5D) Score; European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30); European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23).
2. Correlation of efficacy measures with tumour Biomarkers, including PgR IHC status (10% cut-off), the SET index (gene expression including ESR1 RNA mutation at LBD), ESR1 DNA somatic mutation status, and other pre-defined biomarkers that are relevant to the treatments in the trial. (e.g. CCND1, CDKN2A, PIK3CA, Ki67).
3. Overall survival (OS) and 1- and 2-year OS probabilities
Secondary endpoints
4. Objective response (OR) assessed by RECIST 1.1
5. Duration of response
6. Clinical Benefit Rate (CBR: CR + PR + SD > 24 weeks)
7. Frequency and grade (according to CTCAE v. 4.0, see Appendix) of adverse events (AE) and their relation to study treatment and procedures.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for evaluation of secondary endpoints from blood and tissue samples will be identical to those decribed in 23.1 for Primary endpoint.
Quality of Life Questionnaires (patient reported outcomes) to be completed at clinic • Before starting study treatment and
• Before each cycle for the first 12 weeks, then at each radiological evaluation (every 12-16 weeks).
• When study treatment finishes
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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