To describe and compare pharmacokinetics of everolimus in a 10 mg QD and everolimus 5mg BID schedule, evaluated PK parameters will be a.o. Cmax/Cmin ratio, AUC, Cmax, Cmin, Tmax.
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetics of 10 mg QD vs 5 mg BID Everolimus: evaluated PK parameters
will be a.o. Cmax/Cmin ratio, AUC, Cmax, Cmin, Tmax.
Secondary outcome
Incidence and severity of stomatitis and other adverse events between the two
dosing schedules, according to CTC-AE v4.03.
Exploratory objective: Quantifying Everolimus in the oral fluid of patients.
Background summary
The hypothesis of this study is that dosing everolimus 5mg twice daily(BID)
instead of 10 mg once daily (QD) decreases the incidence of side effects, as a
result of a lower Cmax while maintaining Cmin and AUC.
Everolimus is an effective oral drug with a sometimes challenging safety
profile. In clinical practice a substantial number of patients has dose
limiting or quality of life reducing side effects.
Some everolimus side effects (like stomatitis) may be Cmax driven. Stomatitis
(any grade) occurs in more than half of all patients treated with 10 mg
Everolimus QD. An incidence of 56% was reported in the BOLERO-2 trial by
Baselga et al and 57% in a meta-analysis of oncology trials with everolimus in
pNET, RCC, NSCLC and carcinoid by Raveaud et al. Grade 3-4 stomatitis occurred
in 8% (Baselga et al) and 6% (Ravaud et al) of patients in these studies.
Considering the pharmacological properties of everolimus, we hypothesize that
this decrease in Cmax (while maintaining Cmin and AUC) can also be established
by dividing the standard everolimus tablets over the day (upholding the same
daily dose).
We suggest to perform a study measuring everolimus pharmacokinetics during
twice daily dosing of 5 mg of standard everolimus tablets and compare this with
PK data derived from once daily dosing of 10 mg of standard everolimus tablets.
If the Cmax in the BID schedule is reduced whilst maintaining Cmin and AUC,
spreading intake moments of everolimus over the day might reduce adverse events
without compromising treatment efficacy.
Study objective
To describe and compare pharmacokinetics of everolimus in a 10 mg QD and
everolimus 5mg BID schedule, evaluated PK parameters will be a.o. Cmax/Cmin
ratio, AUC, Cmax, Cmin, Tmax.
Study design
Pharmacokinetic cross over trial of Everolimus 10 mg QD vs 5 mg BID.
Intervention
2 weeks of treatment with 5 mg BID Everolimus (+ 25 mg QD Exemestane).
Study burden and risks
Blood samples voor pharmacokinetic analysis and lab assessments (max 160 ml).
Additional hospital visits (2 overnight stays and 2 outpatient visits).
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1.Age >= 18 years;
2.Able and willing to give written informed consent;
3.Able and willing to undergo blood sampling for PK analysis;
4.Histopathologically confirmed advanced hormone positive, HER2 negative, breast cancer for which everolimus in combination with exemestane is considered standard of care.
5.Minimal acceptable safety laboratory values
a.ANC of >= 1.5 x 10^9 /L
b.Platelet count of >= 100 x 10^9 /L
c.Hepatic function as defined by serum bilirubin <= 1.5 x ULN, ASAT and ALAT <=2.5 x ULN
d.Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 mL/min (by Cockcroft-Gault formula);
Exclusion criteria
1.Woman who are pregnant or breast feeding;
2.Known hypersensitivity to any of the study drugs or excipients;
3.Unable or unwilling to undergo pharmacokinetic sampling;
4.Use of any concomitant medication (including OTC and herbal medication) which may induce or inhibit function of CYP3A4, including but not limited to efavirenz, etravirine, nevirapine, rifampicine, boceprevir, claritromycine, elvitegravir, erytromycine, fluconazol, itraconazol, ketoconazol, posaconazol, telaprevir, verapamil, cyclosporine, voriconazol, dexamethason, St John*s Wort and grapefruit juice;
5.Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the investigator would impair study compliance;
6.Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications;
7.Legal incapacity
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 | EUCTR2014-004833-25-NL |
| CCMO | NL51475.031.14 |