| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Everolimus/ribociclib cohort (D-IVa):
Postmenopausal female patients with hormone-receptor positive, HER2-negative metastatic breast cancer with HER2-negative circulating tumor cells (CTCs) and indication for standard endocrine therapy.
Eribulin cohort (D-IVb):
Patients with hormone-receptor positive, HER2-negative metastatic breast cancer and indication to chemotherapy or patients with triple-negative metastatic breast cancer, both with HER2-negative circulating tumor cells (CTCs).
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with HER2-negative metastatic breast cancer and persisting HER2-negative circulating tumor cells (CTCs). |
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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 |
Everolimus/Ribociclib cohort (DIVa)
The primary objective is to investigate the clinical efficacy of everolimus/ribociclib (as assessed by the CTC clearance rate) in combination with endocrine therapy in postmenopausal patients with hormone-receptor positive, HER2-negative metastatic breast cancer and persisting HER2-negative circulating tumor cells (CTCs).
Eribulin cohort (DIVb)
The primary objective is to investigate the clinical efficacy of eribulin (as assessed by progression-free survival, PFS) both in patients with HER2-negative, hormone-receptor positive metastatic breast cancer and indication to chemotherapy and triple-negative metastatic breast cancer both with persisting HER2-negative CTCs.
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| E.2.2 | Secondary objectives of the trial |
• Evaluation of efficacy of the study treatment as assessed by overall response rate (ORR), disease control rate (DCR), and overall survival (OS)
• Assessment of the dynamic of CTCs by longitudinal comparisons of CTC counts before during and after treatment and evaluation of the value of different measures of CTC dynamics for prognosis and assessing therapy efficacy
• Assessment of Quality of Life (QoL) as evaluated based on the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires
• Assessment of quality-adjusted survival (as calculated by the Q-TWiST method)
• Assessment of toxicity, safety and tolerability of the study treatments (everolimus/ribociclib or eribulin)
• Evaluation of compliance to study procedures
• Evaluation of efficacy of the study treatment as assessed by progression-free survival (PFS) (Everolimus/Ribociclib cohort (DIVa)) |
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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 |
TRAFO-Projects:
Everolimus/Ribociclib cohort (DIVa):
• Establishing of immune histochemistry and assessment of the response of phosphorylated ribosomal protein S6 (pS6) analysed in CTCs to treatment
• Evaluation of the correlation of pS6 levels analysed in CTCs with clinical outcome (PFS)
• Assessment of the activation of the PI3K/Akt/mTOR-pathway in CTCs (SNaPshot methodology for PI3KCA mutations)
• Establishing and assessment of immune histochem-istry for pAKT and PTEN in CTCs
• Establishing the analysis of estrogen-receptor 1 (ESR-1) mutations via SNaPshot methodology in CTCs
• Expression of Epithelial Mesenchymal Transition inducing transcription factors in CTCs
• Resistance to anoikis in CTCs
• Expression of LKB1 in CTC
• Molecular profiling of CTCs in breast cancer
• Quantification of circulating microRNAs miR-125a, miR-125b, miR-18a und miR18b in the serum of breast cancer patients
Eribulin cohort (DIVb)
• Evaluation of efficacy of the study treatment as assessed by new metastasis-free survival (nMFS)
• To determine the androgen receptor (AR) expression on CTCs using AR specific monoclonal antibody
• To determine mutation status of AR by PCR amplification of AR exons followed by sequencing analysis
• To determine PIK3CA mutations on CTC based on SNaPshot technology
• To isolate Eribulin resistant CTCs from TNBC patients and to characterize them on the molecular level with a special focus on the correlation between EMT and their capacity to overcome anoikis.
• To determine the predictive values of the detection of aberrant 53BP1 signals on CTCs and genetic alterations in BRCA1 in peripheral blood samples as potential biomarkers for responsiveness to therapy with Eribulin in patients with TNBC and persisting HER2-negative CTCs.
• To assess the dynamic of 53BP1 signals on CTCs by longitudinal comparisons before, during, and after treatment, to evaluate the suitability of the different measures for assessing therapy efficacy |
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| E.3 | Principal inclusion criteria |
In general:
1. Metastatic breast cancer, which cannot be cured by surgery or radiotherapy. The primary tumor and/or biopsies must have be confirmed as cancer by histolopathology.
2. HER2 status (as investigated on all primary tumor tissue and/or biopsies from metastatic sites or loco regional recur-rences) must be negative. HER2-negativity is defined as (i.e.: immunohistochemistry (IHC) score 0-1+ or 2+ and fluorescent in situ hybridization (FISH) negative or just FISH negative, whichever was performed) in all tissue samples.
3. Evidence of CTCs. At least one CTC has been detected in 7.5 ml patient blood by means of the CellSearch® Circulating Tumor Cell Kit (Veridex LLC, Raritan, USA).
4. HER2 negativity of all detected CTCs.
5. Adequate organ function within 7 days before date of recruitment.
6. Written informed consent in study participation.
7. Undergoing a re-biopsy prior to inclusion if tissue is accessible, which can be safely biopsied, is otional but desirable.
8. Tumor evaluation has been performed within 6 weeks before date of recruitment and results are available.
9. Patients must have at least one not previously irradiated lesion that can be evaluated according to RECIST version 1.1 (Eisenhauer 2009). Patients with measurable and non-measurable disease are eligible. Presence of clinically and/or radiologically documented disease.
10. Age ≥ 18 years.
11. ECOG Performance Status ≤ 2.
Everolimus/ribociclib cohort (DIVa)
• Indication for an endocrine therapy (Histological confirmation of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+) breast cancer).
• Up to two lines of previous cytostatic treatment for MBC.
• Any endocrine therapy in the history is allowed.
• Cholesterol ≤ 2.0 × ULN.
• Disease progression following prior treatment with endocrine therapy (endocrine therapy does not have to be the last therapy before inclusion in the trial).
• Postmenopausal women. The investigator must confirm postmenopausal status
Postmenopausal status is defined either by
- Age ≥ 55 years and one year or more of amenorrhea
- Age < 55 years and one year or more of amenorrhea and postmenopausal levels of FSH and LH
- Prior hysterectomy and has postmenopausal levels of FSH and LH
- Surgical menopause with bilateral oophorectomy
Everolimus cohort:
• Cholesterol ≤ 2.0 × ULN
Ribociclib cohort:
• Standard 12-lead ECG values assessed by the local laboratory:
- QTcF interval at screening < 450 msec (us-ing Fridericia’s correction)
- Resting heart rate 50-90 bpm
• INR ≤ 1,5 (ribocilclib cohort)
• Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplemets before the first dose of study medication:
-Sodium
-Potassium
-Total calcium
Eribulin cohort (DIVb)
• Either hormone-receptor negative MBC or hormone-receptor positive MBC with indication for chemotherapy
• Up to three previous chemotherapy treatment lines for metastatic disease
• In case of patients of child bearing potential:
- Negative pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) within 7 days prior to recruitment
- Contraception by means of a reliable method (i.e. non-hormonal contraception, IUD, a double barrier method, vasectomy of the sexual partner, complete sexual abstinence). Patient must consent in maintaining such contraception until 3 months after completion of study treatment |
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| E.4 | Principal exclusion criteria |
In general:
1. Treatment with other investigational agents of any type or anticancer therapy during the trial, within 2 weeks prior to the start of treatment.
2. Adverse events due to prior anticancer therapy which are > Grade 1 (NCI CTCAE) and therapeutically relevant at time of treatment start.
3. Known HIV infection.
4. Current active hepatitis B or C, cliniclally relevant known liver dysfunction, e.g. known liver dysfunction according to Child Pugh Classification class B and C, or biliary disease (with exception of patients with Gilbert‘s syndrome, asymptomatic gall-stones, liver metastases or stable chronic non-viral liver disease per investigator assessment).
5. Concurrent disease or condition that might interfere with adequate assessment or evaluation of study data, or any medical disorder that would make the patient‘s participation unreasonably hazardous.
6. Other malignant diseases within the last 3 years (apart from carcinoma in situ of the cervix or non-melanoma skin cancer)
7. Dementia, altered mental status, or any psychiatric or social condition which would prohibit the understanding or rendering of informed consent or which might interfere with the patient‘s adherence to the protocol.
8. Life expectancy < 3 months.
9. Male gender.
Everolimus/Ribociclib cohort (DIVa)
• Known hypersensitivity to any of the excipients of ribociclib, everolimus or any of the other given drugs.
• Known hypersensitivity to lecithin (soya) and peanuts (ribocilib-cohort)
• Disease or condition, which might restrain the ability to take or resorb oral medication. This includes malabsorption syndrome, requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption (for example resection of small bowel or stomach), uncontrolled inflammatory GI disease (e.g., Crohn‘s disease, ulcerative colitis) and any other diseases significantly affecting gastrointestinal function as well as inability to swallow and retain oral medication for any other reason.
Eribulin cohort (DIVb)
• History of hypersensitivity reactions attributed to eribulin.
• Pre-existing neuropathy grade 3 or higher.
• Severe Congenital long QT syndrome.
• Pregnancy or nursing. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Everolimus/Ribociclib cohort (DIVa)
CTC clearance rate: Proportion of patients with at least one CTC detected in 7.5 ml of peripheral blood drawn before treatment that show no evidence of CTCs in the blood after treatment (CTC prevalence as assessed using the Cell-Search® System; Veridex LLC, Raritan, USA)
Eribulin cohort (DIVb)
The primary endpoint is progression-free survival (PFS), defined as time interval from date of recruitment until progressive disease (PD) or death from any cause, whichever comes first (as defined by RECIST guideline version 1.1). If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
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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) |
In General:
• Overall response rate (ORR): rate of complete (CR) and partial responses (PR) in patients in whom target lesions were defined
• Disease control rate (DCR): rate of patients who were assessed as having a PR or a CR or who had stable disease (SD) for at least 6 months
• Overall survival (OS), defined as the time interval from start of treatment until death due to any cause. If a patient is not known to have died, survival is censored at the date of last contact
• Dynamic of CTC: Descriptive statistics of regular CTC counts
• Level of compliance to the study protocol
• The assessment of safety will be based mainly on the frequency of adverse events. Other safety data (e.g. laboratory values, vital signs, and special tests) will be considered as appropriate
• Quality of life (QoL) as assessed by evaluation of the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires
• Quality-adjusted survival (as assessed by the Q-TWiST method), with the utility scores for the different health states being prospectively determined in the clinical trial subjects based on the EORTC QOL C30 questionnaire
Everolimus/Ribociclib cohort (DIVa)
• Progression-free survival (PFS), defined as time interval from date of recruitment until progressive disease (PD) or death from any cause, whichever comes first (as defined by RECIST guideline version 1.1).
• Dynamic of CTCs: changes in CTC counts from baseline numbers (start of treatment) to the time of first radiological tumor evaluation after about 12 weeks, and every 12 weeks thereafter until progression
• Levels of pS6 at baseline, at first radiological tumor assessment after about 12 weeks, and at the time of progression
• Change in the activation of the PI3K/Akt/mTOR-pathway in CTCs as assessed by longitudinal comparisons (at baseline, after 12 weeks, at time of progression)
• Estrogen-receptor 1 (ESR-1) mutations in CTCs at baseline, after 12 weeks and at time of progression
Eribulin cohort (DIVb)
• Dynamic of CTCs: changes in CTC counts from baseline numbers (start of treatment) to first (6 weeks) and second (12 weeks) control visit as well as the time of progression or end of treatment.
• New metastasis-free survival (nMFS), defined as time from recruitment to death or progression due to appearance of a new metastasis, whichever comes first. If a patient has not had an event, nMFS is censored at the date of last adequate tumor assessment.
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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 | 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| 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 | 100 |
| E.8.5 | The trial involves multiple Member States | No |
| 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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| LPLV (last patient last visit) |
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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 | 9 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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