Open, multicenter phase I with gradual increase in dosage to evaluate the safety and
tolerability of orally administered nintedanib plus letrozole orally (2.5 mg / day) for
patients with breast cancer. Nintedanib is administered twice a day orally for 28 consecutive
days (Days 1-28) in 4-week cycles.
Phase 0 / I:
At level 1 it includes three patients. If any patient suffers dose limiting toxicity (DLT),
it proceeds to the increase in dose to the next level. If 2/3 patients experience DLT, he
will close the increased dose and extended / investigate the previous dose level with 3
additional patients.
If the level 2, but less than 1/3 the minimum of 6 patients experience TLD is reached, the
phase I be suspended because not expected another rise above Level 2.
Dose levels:
- Level 1: Nintedanib 150 mg twice daily + oral letrozole 2.5 mg / day orally, in a cycle
of 28 days.
- Level 2: Nintedanib 200 mg twice daily via oral + letrozole 2.5 mg / day orally, in a
cycle of 28 days.
- At least the first cycle will be administered during Phase I. A total of six four-week
cycles were administered at the discretion of the investigator.
Inclusion Criteria:
1. Form signed informed consent.
2. Women ≥ 18 years.
3. Confirmed diagnosis of invasive non-metastatic breast cancer positive for hormone
receptors. The inclusion of patients with ductal or lobular histology allowed.
4. Size greater than 1 cm tumor and any N or N ≥ 1 and any T, including inflammatory
breast cancer.
5. Absence of metastatic involvement.
6. Postmenopausal state. Postmenopausal status is defined as more than 24 months after
the last menstrual period, or previous known ovariectomy, or chemical, determined by
FSH, LH and estradiol 17-B according to the local laboratory values over 12 months
without menstruation.
7. ECOG performance status of 0 or 1
8. At least one month after the end of radiotherapy and / or chemotherapy.
9. At least 6 weeks since major surgery.
10. Patients currently treated with letrozole less than 6 months.
11. Primary surgery for breast cancer already done. The elderly women with advanced local
or regional tumors in which hormone treatment is administered as monotherapy,
regardless of the intent of the surgery are not candidates.
12. LVEF> 50%
13. Renal function, liver and adequate hematologic, defined by the following analytical
results within 14 days prior to randomization or registration:
- Absolute granulocyte count> 1.5 x 109 / L
- Absolute platelet count> 100 x 109 / L
- Hemoglobin> 10 g / dl
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance> 50 ml / min
- Serum bilirubin <1.25 ULN
- AST / ALT ≤ 1.5 times the LS
14. Toxicities associated with chemotherapy recovery lesser extent 2 not tolerable.
15. Life expectancy> 6 months.
Exclusion Criteria:
1. HER2 overexpression defined as positive by immunohistochemistry HER-2-positive 2+ 3+
or FISH / CISH.
2. Absence of tumor tissue file.
3. T1 N0 stage patients are excluded.
4. Malignancy concomitant active, or diagnosis of another malignancy within the last five
years, apart from non-melanoma or ductal / tubular breast carcinoma skin cancer (not
received hormone treatment) or in situ cervical cancer, carcinoma colon in situ
treated properly, as well as any diagnosis of tumor less than five years before the
inclusion unsigned progression today.
5. Women of childbearing potential.
6. Pretreatment nintedanib. Use of other investigational drugs during the administration
of adjuvant or neoadjuvant treatment is not an exclusion criterion as long as toxicity
recovers.
7. Medical Condition concomitant serious, like eg myocardial infarction within 6
uncontrolled prior to inclusion in the study months, congestive heart failure,
unstable angina, cardiomyopathy active, unstable ventricular arrhythmia, hypertension
(according to the criteria of the NYHA) , psychotic disorders uncontrolled severe
active infections, active peptic ulcer disease, psychiatric disease, HIV infection,
active hepatitis, COPD or any other medical condition that might be aggravated by
treatment or limits compliance.
8. Inability to make oral, or history of malabsorption syndrome medication.
9. Failure to comply with the study and follow-up procedures.
10. Anticoagulant therapy (except low-dose heparin or heparin washing as needed to
maintain a permanent intravenous device) or antiplatelet therapy (except low-dose
therapy with aspirin, less than 325 mg daily).
11. History of thromboembolic or hemorrhagic episodes that are clinically relevant in the
past 6 months or hereditary predisposition to bleeding or thrombosis.
12. Contraindication to hormonal blockade or absence of hormone-blocking prescription from
your doctor for any reason. Metastatic breast cancer or non-surgical (including
inflammatory).
