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Nintedanib+Letrozole in Postmenopausal Women With Breast Cancer: Clinical Trial Safety and Pharmacodynamics

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ClinicalTrials.gov Identifier: NCT02619162
Recruitment Status : Completed
First Posted : December 2, 2015
Last Update Posted : July 23, 2019
Dr. Miguel Angel Quintela Fandiño (CNIO)
Dr, Ramón Colomer i Bosch
FUNDACIÓN CRIS (Marta Cardona) as promotor
Information provided by (Responsible Party):
Centro Nacional de Investigaciones Oncologicas CARLOS III

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Nintedanib Drug: Letrozole Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nintedanib Plus Letrozole in Postmenopausal Women With Breast Cancer: Clinical Trial Phase 0/1 Safety and Pharmacodynamics
Actual Study Start Date : July 2015
Actual Primary Completion Date : November 2017
Actual Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Letrozole+Nintedanib
Drug: Nintedanib
Tablets of 100 mg. or 150 mg.
Other Name: BIFF 1120

Drug: Letrozole
Tablet of 2.5 mg.

Primary Outcome Measures :
  1. Dose limiting toxicity [ Time Frame: 1-6 months ]
    Classified according to the version 4.03 of CTCAE criteria NCI1

Secondary Outcome Measures :
  1. Evaluating FGFR1 modulation and inhibition levels of 17-B Estradiol [ Time Frame: 1-6 months ]
    Assess the pharmacodynamic modulation of FGFR1 and inhibition levels of 17-B: determine plasma levels of FGF 23 ang 17- B estradiol (pg/mL)

  2. Pharmacokinetic interactions [ Time Frame: 29 days ]
    Determine the pharmacokinetic interactions nintedanib combined with letrozole: determine plasma levels of Nintedanib and Letrozole at day 0, day 15 and day 29 (Cmax)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02619162

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Hospital Universitario de Fuenlabrada
Fuenlabrada, Madrid, Spain, 28942
Hospital de La Princesa
Madrid, Spain, 28006
Clínica Quirón
Madrid, Spain, 28223
Sponsors and Collaborators
Centro Nacional de Investigaciones Oncologicas CARLOS III
Dr. Miguel Angel Quintela Fandiño (CNIO)
Dr, Ramón Colomer i Bosch
FUNDACIÓN CRIS (Marta Cardona) as promotor
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Study Chair: Marta Cardona Fundacion CRIS de Investigación para Vencer el Cáncer
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Centro Nacional de Investigaciones Oncologicas CARLOS III
ClinicalTrials.gov Identifier: NCT02619162    
Other Study ID Numbers: CNIO-BR-007
First Posted: December 2, 2015    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019
Keywords provided by Centro Nacional de Investigaciones Oncologicas CARLOS III:
breast cancer non metastatic
adjuvant letrozole
Nintedanib BIFF1120
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Protein Kinase Inhibitors