| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Breast Cancer, HER-2 Negative, Hormone receptor positive |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To demonstrate the superiority of palbociclib in combination with fulvestrant (with or without goserelin) over fulvestrant (with or without goserelin) alone in prolonging investigator-assessed PFS in women with HR+/HER2- metastatic breast cancer whose disease has progressed on prior endocrine therapy |
|
| E.2.2 | Secondary objectives of the trial |
- To compare measures of tumor control (including PFS, DR, CBR) between the treatment arms.
- To compare safety and tolerability between the treatment arms.
- To evaluate trough concentrations of palbociclib when given in combination with fulvestrant or fulvestrant plus goserelin compared to historical palbociclib data.
- To compare fulvestrant and goserelin trough concentrations when given in combination with palbociclib to those when given without palbociclib.
- To explore correlations between palbociclib exposures and efficacy/safety findings in this patient population.
- To compare Patient Reported Outcomes measures between treatment arms.
- To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle, drug targets, tumor sensitivity and/or resistance.
- To conduct subgroup analysis for primary and secondary endpoints in stratified groups. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Women 18 years of age or older, who are either:
- Postmenopausal, as defined by at least one of the following criteria:
- Age ≥ 60 years;
- Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and FSH level within the laboratory’s reference range for postmenopausal females;
- Documented bilateral oophorectomy;
- Medically confirmed ovarian failure.
OR
- Pre/peri-menopausal, ie, not meeting the criteria for being postmenopausal.
- Pre/perimeopausal women can be enrolled if amenable to be treated with the LHRH agonist goserelin. Patients must have commenced treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to randomization. But, if patients have received an alternative LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial.
2. Histologically or cytologically proven diagnosis of breast cancer with evidence of metastatic or locally advanced disease, not amenable to resection or radiation therapy with curative intent.
3. Documentation of ER-positive and/or PR-positive tumor (≥1% positive stained cells) based on most recent tumor biopsy (unless bone-only disease, see below) utilizing an assay consistent with local standards.
4. Documented HER2-negative tumor based on local testing on most recent tumor biopsy: HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or for single probe assessment a HER2 copy number <4.
5. Patients must satisfy the following criteria for prior therapy:
- Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre- or perimenopausal.
OR
- Progressed while on or within 1 month after the end of prior aromatase inhibitor therapy for advanced/metastatic breast cancer if postmenopausal, or prior endocrine treatment for advanced/metastatic breast cancer if pre- or perimenopausal.
One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy.
6. Except where prohibited by local regulations, all patients must agree to provide and have available a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken at the time of presentation with recurrent or metastatic disease. A de novo biopsy is required,- if no archived tissue taken at the time of presentation with recurrent/metastatic disease is available. The sole exception is those patients with bone only disease for whom provision of previous archival tissue only is acceptable. Patients, who had surgery within the last 3 years (but without neoadjuvant chemotherapy prior to surgery) and elapsed while receiving adjuvant therapy may provide a tumor specimen from that surgery.
7. Measurable disease as defined by RECIST version 1.1, or bone-only disease. Patients with bone-only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by CT or MRI. Patients with bone-only disease and blastic-only metastasis are not eligible. Tumor lesions previously irradiated or subjected to other loco
regional therapy will only be deemed measurable if progression at the treated site after completion of therapy is clearly documented.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
9. Adequate organ and marrow function defined as follows:
- ANC ≥1,500/mm3 (1.5 x 109/L);
- Platelets ≥100,000/mm3 (100 x 109/L);
- Hemoglobin ≥ 9 g/dL (90 g/L);
- Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution;
- Total serum bilirubin ≤1.5 x ULN (<3ULN if Gilbert’s disease);
- AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);
- Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN if bone or liver metastases present).
10. Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade ≤1 (except alopecia).
11. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
12. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with any CDK inhibitor, or fulvestrant, or with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway.
2. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement).
3. Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy,
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
4. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers (for examples, see the Prohibited Medications section), and drugs that are known to prolong the QT interval.
5. Major surgery, chemotherapy, radiotherapy, or other anti cancer therapy within 2 weeks before randomization. Patients who received prior radiotherapy to ≥ 25% of bone marrow are not eligible independent of when it was received.
6. Any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
7. QTc interval >480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
8. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
9. Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of palbociclib, such as history of GI surgery with may result in intestinal blind loops and patients with clinically significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhea of CTCAE Grade >1.
10. Prior hematopoietic stem cell or bone marrow transplantation.
11. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or goserelin (if applicable).
12. Known or possible hypersensitivity to fulvestrant, goserelin, any of their excipients or to any palbociclib/placebo excipients.
13. Known human immunodeficiency virus infection.
14. Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
15. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
16. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks before randomization in the current study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Progression-Free Survival (PFS) as assessed by the Investigator |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After discontinuation of study treatment, post-study survival status (including start, stop and type of post study anticancer therapies) will be collected every 3 months (ie, month 3, 6, and 9, +/-14 days) then every 6 months starting at Month 15 (+/-14 days) from the last dose of study treatment. For patients who discontinue study treatment due to objective disease progression, survival data (ie, patient status, onset and duration of new anticancer therapy) will be collected every 3 months for the first 9 months (ie, Month 3, 6, and 9, +/-14 days), then every 6 months starting at Month 15 (+/-14 days), calculated from the last dose of study treatment. |
|
| E.5.2 | Secondary end point(s) |
- Overall Survival (OS).
- 1-year, 2-year, and 3-year survival probabilities.
- Objective Response (OR: CR or PR).
- Duration of response (DR).
- Clinical Benefit Response (CBR: CR or PR or SD ≥24 weeks).
- Type, incidence, severity (as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), seriousness and relationship to study medications of AEs and any laboratory adnormalities.
- Trough plasma concentration of palbociclib, fulvestrant and goserelin (if applicable) in the subgroup of approximately 40 patients included in the initial safety assessment.
- PRO endpoints such as 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); minimally important difference (MID) cut-off, and time to deterioration (TTD) composite endpoint.
- Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1 and CDKN2A, PIK3CA mutations), proteins (eg, Ki67, pRb, CCNE1), and RNA expression (eg, cdk4, cdk6). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| multiple timepoints as per protocol |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Germany |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Portugal |
| Romania |
| Russian Federation |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| End of Trial in all participating countries is defined as last patient follow up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
