| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated metastatic Estrogen Receptor positive (ER+), Human Epidermal Growth Factor Receptor-2 negative (HER2-) breast cancer with visceral involvement. |
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| E.1.1.1 | Medical condition in easily understood language |
| Untreated metastatic Estrogen Receptor positive (ER+), Human Epidermal Growth Factor Receptor-2 negative (HER2-) breast cancer with visceral involvement. |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective is to compare the efficacy of standard Endocrine Therapy + Abemaciclib combination versus standard Chemotherapy based on progression-free survival (PFS) within 24 weeks, in patients with visceral metastases of ER+ HER2- breast cancer, high tumor burden. |
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| E.2.2 | Secondary objectives of the trial |
•To compare between the 2 study arms:
1. Health-Related Quality of Life (HRQOL) and Patient Reported Outcomes (PRO),
2. Objective response rate (ORR) and duration of response (DoR),
3. Progression-free-survival 1 (PFS 1),
4. Progression-free-survival 2 (PFS 2),
5. PFS1 and PFS2 in prespecified subgroups defined by stratification factors,
6. Overall survival (OS),
7. Safety.
• In patients randomized in Chemotherapy arm: to describe the maintenance regimens administered after the end of the standard treatment by chemotherapy and in the absence of disease progression.
• To study the predictive and prognostic value of circulating tumor cell count (< 5 versus >= 5 CTC/7.5mL) assessed at baseline.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must have signed a written informed consent form prior to any study specific procedures.
2. Female age ≥ 18 years.
3. Performance status, ECOG 0-2.
4. Histologically confirmed adenocarcinoma of the breast.
5. Metastatic breast cancer, with liver and/or lung and/or pleural and/or peritoneal metastases with high tumor burden (according to RECIST v1.1) defined as either:
o visceral involvement of one site with more than 3 lesions,
o visceral involvement of at least 2 sites,
o symptomatic ascites or pleural effusion, defined as the need for weekly drainage with visceral measurable metastases,
o visceral involvement and LDH > N.
6. Patient considered candidate for a first line chemotherapy in metastatic setting by their physician (either capecitabine or paclitaxel) and who may receive first-line endocrine therapy combined with abemaciclib according to the marketed authorization.
7. ER-positive by IHC (>10%) on primary or metastatic disease.
8. HER2-negative by IHC (score 0 or 1+) and/or Fish/Cish negative.
9. Non-menopausal women will receive LH-RH agonists at least 1 month before starting the endocrine therapy and every 28 days thereafter.
10. Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria:
o Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥ 1.5 G/L
o Platelets ≥ 100,000/mm3 or ≥ 100 G/L
o Hemoglobin ≥ 8 g/dL (patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion).
o Serum Aspartate Transaminase (AST) and serum Alanine Aminotransferase Transaminase (ALT) ≤ 3 x upper limit of normal (ULN) (< 5 ULN if liver metastasis)
o Total serum bilirubin ≤ 1.5 x ULN (patients with Gilbert’s syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted)
o Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min as calculated using the standard method for the institution.
11. Adequate cardiac functions, including:
o 12 Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention.
o QTcF interval ≤ 480 msec (mean of replicate values, correction per institutional standard)
o no history of Torsades de Pointes or other symptomatic QTc abnormality.
12. Women of childbearing potential agreeing to use highly effective contraception during treatment and for 3 weeks following the last dose of abemaciclib or for 6 months following the last dose of capecitabine or paclitaxel.
13. Women of childbearing potential must have a negative serum pregnancy test within 7 days and/or urine pregnancy test 48 hours prior to the administration of any study treatment.
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
15. Health insurance coverage. |
|
| E.4 | Principal exclusion criteria |
1. Bone lesion only or non-measurable lesion (RECIST V1.1).
2. Patients with all target lesions in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them.
3. Spinal cord compression and/or symptomatic or progressive brain metastases (Brain metastasis are not acceptable unless asymptomatic or treated and stable off steroids for at least 30 days prior to start of study drug).
4. Patient with visceral crisis as defined in the 4th ESO–ESMO International Consensus Guidelines (severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease).
5. Patient has received one line of chemotherapy for metastatic disease.
6. Patient has received endocrine therapy for metastatic disease.
7. Inability to swallow orally administered medication.
8. Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomization.
9. Major problem with intestinal absorption.
10. Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix or the breast, and adequately treated basal cell or squamous cell carcinoma of the skin.
11. Patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
12. Patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
13. Patient has any serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30 mL/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
14. Any drug or plant derivative that may interact with abemaciclib.
15. Episode of pulmonary thromboembolism (PTE) in the last six months. Patients with deep vein thrombosis previously treated with a low-molecular-weight heparin for more than two months prior enrolment in the study will be eligible.
16. Patients with previously documented total/partial dihydropyrimidine dehydrogenase (DPD) deficiency or with DPD deficiency identified at baseline visit (plasma uracil concentration ≥ 16 ng/mL). These patients will be not eligible for chemotherapy by capecitabine.
17. Pregnant or breast feeding women.
18. Patients enrolled in another therapeutic study within 30 days prior inclusion.
19. Individuals deprived of liberty or placed under the authority of a tutor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) within 24 weeks will be measured from the date of randomization until the date of event defined as the first documented progression (RECIST v1.1) or death from any cause.
Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment or at 24 weeks whichever comes first. The patients free of progression who switched to another therapy before 24 weeks will be censored at the time of the treatment change.
Evaluation will be done by local investigator using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• In both arms throughout treatments:
1. EORTC QLQ-C30 and QLQ-BR23 questionnaires will be used in the measurement of patients’ quality of life. All dimensions will be available at baseline and every 6 weeks during 24 weeks. G8 questionnaire will also be requested at baseline for patient older than 70.
2. Radiological response rates in each treatment arm will be determined according to RECIST v1.1:
. The overall response rate (ORR) will be defined as the proportion of randomized patients who achieve a complete response (CR) or a partial response (PR) at 24 weeks.
. The duration of response (DoR) will be defined as the duration between the time of tumor response (CR or PR) until the date of objective progression.
3. PFS1: Defined as the interval between the date of randomization and the date of progression or death from any cause regardless of whether the patient withdraws from randomized study treatment or receives another anti-cancer therapy prior to progression
4. PFS2 : Time from randomization to second progression is defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the primary variable PFS, or date of death (i.e., objective radiological, CA15-3 or symptomatic progression).
5. PFS1 and PFS2 in subgroups defined by stratification factors.
6. Overall survival (OS) is defined as the interval between the date of randomization and the date of death from any cause.
7. Safety will be evaluated according to the CTCAE V5.0.
• In patients randomized in Chemotherapy arm: Type of maintenance regimens administered after the end of the standard treatment by chemotherapy and in the absence of disease progression.
• Serial CTC counts will be performed using the CellSearch® system on blood samples to assess predictive and prognostic value of CTC status on overall response rate, PFS within 24 weeks, PFS1 and PFS2 respectively. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 36 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | 72 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 72 |
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