Primary objective:Analyze the value of pneumoproteins, everolimus exposure, pulmonary function tests, distinct radiological patterns, baseline patient characteristics and the development of skin toxicity or oral mucositis for the prediction of the…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Find the correlation between:
- baseline patient characteristics (smoking, preexistent lung disease)
- pneumoproteins; KL-6, surfactant protein A, surfactant protein D, CC16,
CCL18, YKL-40, LDH and CA 15.3 (absolute number and difference from baseline)
- everolimus exposure (AUC on day 14 and mini-AUC at moment of toxicity)
- pulmonary function tests: spirometry including FVC and DLCO adjusted for
hemoglobin (absolute number and difference from baseline)
- four distinct radiological patterns of 1.0mm CT slices of the lungs (as
described in paragraph 6.2.7, page 30)
- the development and grade of everolimus-induced skin toxicity and oral
mucositis
and the development and grade of everolimus-induced ILD, using univariate and
multivariate analysis.
Secondary outcome
- Analyze the temporal relationship between a decrease in pulmonary function or
the occurrence of new radiological pulmonary abnormalities and an increase in
the level of pneumoproteins
- Investigate which immunological changes (cytokines, T-cells, dendritic cells)
are observed in peripheral blood, skin biopsies and bronchoalveolar lavage of
patients with everolimus-induced toxicity
- Assess the duration and severity of ILD when patients are treated according
to a standardized diagnostic and treatment strategy
- Define the correlation between everolimus induced ILD on the one hand and
everolimus exposure (as per AUC0-24h) on day 14) and outcome (as per PFS) on
the other hand
- Determine the type and frequency of lung parenchymal changes and its
discriminative power from other (not drug-related) lung changes
- Describe the quantity and quality of differences in judgment of HRCT images
between a local and a central radiologist
- Correlate everolimus exposure in saliva with serum AUC
- Correlate everolimus exposure in saliva with incidence of oral mucositis
Background summary
In postmenopausal women with advanced hormone receptor-positive breast cancer,
treatment with everolimus in combination with exemestane can restore the
sensitivity of the tumor to hormone therapy, and thereby offers an effective
alternative to a chemotherapy regime. The use of everolimus, however, can be
complicated by adverse events such as interstitial lung disease (ILD), i.e.,
pneumonitis. Due to an increased awareness of ILD and inclusion of radiological
findings using high resolution (HR) CT, nowadays ILD is reported in 10-40% of
patients. However, only retrospective studies have been performed. Most
patients are asymptomatic or mildly symptomatic, but in some patients ILD will
cause serious pulmonary problems. Therefore, it is important to enable
discrimination between patients in whom everolimus can be continued safely and
in whom discontinuation is indicated. At this moment no data are available to
aid in this distinction. Early and non-invasive markers that can predict the
development and severity of everolimus-induced ILD would therefore be of great
clinical value.
Additionally, the pathophysiology of everolimus-induced ILD is unclear.
Furthermore, there is no standardized strategy for everolimus induced ILD. A
more thorough understanding of this pathophysiology can aid in the development
of rational and more effective management strategies of this hazardous side
effect.
To resolve these clinically relevant problems prospective data investigating
everolimus-induced ILD are needed, especially in the vulnerable metastatic
breast cancer patient.
Study objective
Primary objective:
Analyze the value of pneumoproteins, everolimus exposure, pulmonary function
tests, distinct radiological patterns, baseline patient characteristics and
the development of skin toxicity or oral mucositis for the prediction of the
development and severity of everolimus-induced ILD.
Secondary objectives:
- Determine whether a decline in pulmonary function test or the occurrence of
new radiological pulmonary abnormalities is preceded by an increase in the
level of pneumoproteins
- Investigate the pathophysiology of everolimus-induced ILD, skin toxicity and
oral mucositis
- Describe the outcomes of a standardized treatment strategy for
everolimus-induced ILD
- Correlate the development and grade of everolimus-induced ILD, skin toxicity
and oral mucositis with everolimus exposure (AUC) and outcome (PFS)
- Determine the type and frequency of lung parenchymal changes and its
discriminative power from other (not drug-related) lung changes
- Determine the impact of radiological interreader variability on patient
management (e.g., expert opinion versus general radiologist)
Study design
This is a prospective post registration, multicenter study. After starting
treatment with everolimus and exemestane patients will be monitored during six
months for the development of pulmonary complications as well as skin toxicity
and oral mucositis. Hereafter patients will be followed until treatment with
everolimus and exemestane is discontinued. The moment and reason for everolimus
and exemestane discontinuation will be recorded.
Study burden and risks
The study procedures will be performed at the moments that patients will visit
their clinic for standard patient care, so no extra visits are needed.
Patients will be asked to keep a diary in which they will record their adverse
events. Extra blood (80 ml per visit) will be drawn on moments where blood is
drawn in standard patient care, therefore no extra venous punctures will be
necessary. Patients will undergo PFT six times for study purposes, which will
take about 15 minutes per PFT. Tumor response with a chest CT will be evaluated
after three and six months of treatment, so no extra CT-scans will be
necessary. From this chest CT 1.0mm CT slices of the lungs will be obtained. No
extra radiation dose or intravenous contrast injection will be necessary. On
day 14 patients have to visit their clinic for PK analysis, where a total of
six blood samples will be taken via an intravenous cannula, up to 8 hours after
everolimus ingestion. In addition, a trough level everolimus will be measured
in saliva.
If ILD or grade * 2 skin toxicity or oral mucositis develops, extra blood (74
ml) will be drawn, PFT will be repeated and a 2-3mm skin biopsy will be
performed if patients agree.
Benefits associated with participating in this study are that patients and
their treating physician will be extra alert on the development of adverse
events, especially ILD. The treating physician is provided with a detailed
management strategy, which aids in treating this toxicity optimally.
In addition, everolimus exposure will be measured. If the treating physician
thinks it is in the best interest of the patient he/she can obtain the results
from the principal investigator and is free to change the dose according to
his/her own judgment.
Geert Grooteplein 10
nijmegen 6500 HB
NL
Geert Grooteplein 10
nijmegen 6500 HB
NL
Listed location countries
Age
Inclusion criteria
Eligible for inclusion are women who are planned to start treatment with everolimus in combination with exemestane as decided by their treating physician, if the patient is willing and able to sign the Informed Consent Form. The following general criteria can be used to determine whether a patient is suitable for treatment with everolimus and exemestane. Renal insufficiency and pulmonary disease are not considered an exclusion criterion.
- Adult women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
- Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
- Postmenopausal women. Postmenopausal status is defined either by:
o Age * 55 years and one year or more of amenorrhea
o Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml
o Surgical menopause with bilateral oophorectomy
- Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment
- Resistance to treatment with a non-steroidal aromatase inhibitor
- Serum platelets * 100x10E9/l
- Everolimus dose adjustment is recommended for patients with hepatic impairment (Child-Pugh A/B/C)
- Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100)
Exclusion criteria
- Patients with a HER2-overexpressing tumor by local laboratory testing (IHC 3+ staining or amplification defined as locus/centromere ratio > 2.2 on fluorescent situ hybridization (FISH) or cytochromic in situ hybridization (CISH))
- Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
- Patients with a known history of HIV seropositivity or hepatitis B or C
- Uncontrolled diabetes mellitus
- Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
- Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002258-60-NL |
| CCMO | NL45027.091.13 |