| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER-2 negative metastatic breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| HER-2 negative metastatic breast cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Population: STEP 1
• To assess the global safety of the combination of palbociclib + endocrine therapy in the whole population of patients, throughout the study, including the potential sequential administration of fulvestrant plus palbociclib, with focus on hematological toxicities.
Population: STEP 2
• To assess whether a change of the hormone therapy associated with palbociclib (namely, an early switch from aromatase inhibitor with palbociclib to fulvestrant with palbociclib following ctDNA detection) will benefit patients in which rising ESR1 mutations are detected during treatment with palbociclib and aromatase inhibitor.
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| E.2.2 | Secondary objectives of the trial |
Population: STEP 1 & 2 – Arm A & B
• To report the efficacy (progression-free survival defined on conventional RECIST criteria) of palbociclib combined with hormone therapy, from the date of initial inclusion into the trial.
Population: STEP 2 & 3 – Arm A & B
• To assess whether, in patients with rising ESR1 mutations, the early switch (switch following ctDNA detection) to fulvestrant leads a longer overall PFS from initial inclusion into the trial, than a late switch (cross-over following RECIST tumor progression).
All Population: STEP 1 to 3
• To obtain additional safety data in a broad patient population treated with palbociclib and hormone therapy in a general oncology practice context, and to study the association with patients' baseline characteristics.
• To study the patient’s reported quality of life before and throughout therapy.
• To report the anti-cancer treatments received after the first line therapy, and the overall survival of included patients. |
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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 study : A prospective cohort to identify mechanisms of resistance to palbociclib
- To define which molecular alterations on tumor biopsy and/or plasma are acquired after resistance to palbociclib and endocrine therapy.
- To identify which molecular alterations on tumor biopsy and/or plasma are associated with early progression to palbociclib and hormone therapy.
- To define whether ctDNA biomarkers other than ESR1 mutations could allow early response assessment and/or early diagnosis of progression. |
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| E.3 | Principal inclusion criteria |
1. Women with proven loco-regionally recurrent or metastatic adenocarcinoma of the breast not amenable to curative therapy with disease considered potentially sensitive to aromatase inhibitors
Note: patients relapsing while on adjuvant tamoxifen or other non-aromatase inhibitor adjuvant endocrine therapy are eligible for the present study; patient relapsing after 6 years or more under adjuvant aromatase inhibitor are eligible.
2. Age ≥18 years;
3. Life expectancy > 3 months;
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
5. Estrogen Receptor (ER)-positive and HER2-negative breast cancer. Where available, assessment of Estrogen Receptor status should be based on the most recent tumor sample; to be considered as ER-positive, the most recent breast cancer tissue examined must display at least 10% of cancer cells with positive ER staining;
6. Tumor block (primary tumor or metastasis) available;
7. No prior systemic anti-cancer therapy for metastatic or advanced disease (chemotherapy, targeted therapy or hormone therapy); prior initiation of LHRH agonist or bone-directed agents is however allowed);
8. Menopausal patients or patients with suppressed ovarian function:
• Women with bilateral oophorectomy
• Postmenopausal women, as defined by any of the following criteria:
- Age 60 or over;
- Age 50 to 59 years and meets one of the following criteria:
- Amenorrhea for ≥ 24 months and follicle-stimulating hormone within the postmenopausal range;
- patients with hysterectomy or chemotherapy-induced amenorrhea must display follicle-stimulating hormone within the postmenopausal range;
• Other women, provided they are being treated with monthly LHRH analogues (first injection performed ≥7 days before the treatment initiation) and are willing to continue to receive LHRH agonist therapy for the duration of the trial;
9. Patients may have measurable (according to Response Evaluation Criterion in Solid Tumors (RECIST v1.1) or not measurable disease
• Patients with only blastic bone lesions are not eligible;
• Patients with only pleural, cardiac or peritoneal effusion or meningeal carcinomatosis are not eligible;
10. Adequate organ and marrow function as defined below:
• Hemoglobin ≥ 90 g/L
• Absolute neutrophil count ≥ 1.5 G/L
• Platelet count ≥ 100 G/L
• Serum bilirubin ≤ 1.5 × ULN. This will not apply to patients with confirmed Gilbert’s syndrome.
• ALT and AST ≤ 3 × ULN;
• Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present)
• Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 60 mL/min as determined by Cockcroft-Gault (using actual body weight) formula for females [creatinine clearance =Weight (kg) × (140 - Age) × 0.85 (mL/min)/ (72 × serum creatinine (mg/dL))
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including screening evaluations;
12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion);
13. Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations;
14. Patient affiliated to a social security system. |
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| E.4 | Principal exclusion criteria |
1. Locally advanced breast cancer or loco-regional relapse amenable for any treatment with curative intent;
2. Her2-positive or equivocal tumor status either on the primary or on the recurrent tumor, defined as IHC3+, Fish/Cish amplified or Fish/Cish equivocal according to the ASCO2015 criteria;
3. Prior endocrine therapy in the metastatic setting is not allowed;
4. Prior treatment with any CDK 4/6 inhibitor in the adjuvant or metastatic setting (neoadjuvant/preoperative treatment is allowed); however, prior therapy with another targeted treatment in the adjuvant setting is allowed;
5. Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that” requires chemotherapy;
6. Any major surgery (defined as requiring general anaesthesia) or significant traumatic injury within 4 weeks of treatment initiation or patients that may require major surgery during the course of the study; however, surgical diagnostic procedure is allowed (even if performed under general anaesthesia);
7. Known, active bleeding diathesis;
8. Any serious known concomitant systemic disorder (e.g. known active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed);
9. Patients unable to swallow tablets;
10. History of mal-absorption syndrome or other condition that would interfere with enteral absorption;
11. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day methylprednisolone equivalent (excluding inhaled steroids);
12. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment start;
13. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, palbociclib or any of their excipients;
14. QTcF >480 msec on basal assessment, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP);
15. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia);
16. Patients treated within the last 7 days prior to treatment start in the trial with drug that are known to be CYP3A4 inhibitors, drugs that are known to be CIP3A4 inducers, drugs that are known to prolong the QT interval; who underwent a grapefruit cure;
17. Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months;
18. History of previous:
• Any other stage II, III, IV cancer within 5 years preceding patient enrollment in the trial – however, multiple primary breast cancers (controlateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+;
• Any history of hematological malignancy;
19. Persons deprived of their freedom or under guardianship or incapable of giving consent;
21. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Hematological safety of patients with bone metastases will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
- Progression-Free Survival (PFS) will be measured from the time of randomization (following rising ESR1 mutation detection) to the time of tumor progression (as assessed by the investigator per RECIST v1.1) or death (whichever comes first) – in randomized patients. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Progression-Free Survival will be measured from the time of inclusion to the time of tumor progression (as assessed by the investigator per RECIST 1.1) or death (whichever comes first) – in all included patients including those switched to fulvestrant (early and late switch).
- Progression-Free Survival will be measured from the time of the randomization to the time of second tumor progression or death (whichever comes first) – in patients proceeded in step 3 (i.e. who did not early switch to fulvestrant+palbociclib after the detection of rising ESR1 mutation).
- Description of all grade 2-4 toxicities and SAEs incidence rate in the overall population and each treatment step.
- Overall Survival measured from the date of inclusion to that of the patient’s death – in all included patients.
- Quality of life score obtained through self-administered QLQ-C30 questionnaire at baseline, at randomization, and every 2 cycles until disease progression (including patients who perform a late switch from arm A to B). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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 | 65 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 | 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
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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 | |
| E.8.9.1 | In the Member State concerned months | 84 |
| E.8.9.1 | In the Member State concerned days | |
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