Several studies have indicated that determining prevalence and number of circulating tumor
cells (CTCs) at various time points during treatment may be an effective tool for assessing
treatment efficacy in metastatic breast cancer (MBC). However, even if the prognostic value
of CTCs in MBC is well understood, the role of both CTC prevalence and CTC phenotype in
predicting treatment response needs further investigation. DETECT IV is a prospective,
multicenter, open-label, phase II study in patients with HER2-negative metastatic breast
cancer and persisting HER2-negative circulating tumor cells (CTCs). Additional research on
CTC dynamics and characteristics will provide a better understanding of the prognostic and
predictive value of CTCs and is one step into a more personalized therapy for MBC.
In General for both study cohorts
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 flu-orescent in situ
hybridization (FISH) negative or just FISH negative, whichever was performed) in all
3. Evidence of CTCs. At least one CTC has been detected in 7.5 ml patient blood by means
of the CellSearch® Circu-lating Tumor Cell Kit (Veridex LLC, Raritan, USA).
4. HER2 negativity of all detected CTCs. HER2-negativity is defined as staining < HER2
5. Adequate organ function within 7 days before date of recruitment, evidenced by the
following laboratory results:
- absolute neutrophil count ≥ 1500/µL
- platelet count ≥ 100000/µL
- hemoglobin ≥ 9 g/dL
- ALT (SGPT) ≤ 3.0 × ULN
- AST (SGOT) ≤ 3.0 × ULN
- bilirubin ≤ 2.0 × ULN
- creatinine ≤ 2.0 × ULN.
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 desira-ble.
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
10. Age ≥ 18 years.
11. ECOG Performance Status ≤ 2.
For Everolimus only:
- 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 amen-orrhea
- Age < 55 years and one year or more of amen-orrhea and postmenopausal levels of
FSH and LH
- Prior hysterectomy and has postmenopausal levels of FSH and LH
- Surgical menopause with bilateral oophorecto-my
For Eribulin only:
- Either hormone-receptor negative MBC or hormone-receptor positive MBC with indication
- 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 dou-ble barrier method, vasectomy of the sexual partner, complete sexual
abstinence). Patient must consent in maintaining such contracep-tion until 3
months after completion of study treatment
In General for both study cohorts:
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.
according to Child Pugh Classifica-tion 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.
For Everolimus only:
- Known hypersensitivity to everolimus or other mTOR inhibitors, e.g. Sirolimus
(rapamycin), or any of the other given drugs.
- Disease or condition, which might restrain the ability to take or resorb oral
medication. This includes malabsorption syndrome, requirement for intrave-nous (IV)
alimentation, prior surgical procedures af-fecting 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
gas-trointestinal function as well as inability to swallow and retain oral medication
for any other reason.
For Eribulin only:
- History of hypersensitivity reactions attributed to eribulin.
- Pre-existing neuropathy grade 3 or higher.
- Severe Congenital long QT syndrome.
- Pregnancy or nursing.