Clinical trial NCT05078671: Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness
Official title: Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Cancer
Keywords: olaparib
pharmacokinetic enhancement
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2021-10-14
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part A: cross-over normal olaparib versus boosted olaparib. Part B: normal olaparib versus boosted olaparib in two patient groups.
Primary purpose: TREATMENT

Brief summary: Olaparib is a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor, originally used for the maintenance treatment of women with platinum-sensitive relapsed breast cancer gene (BRCA)-mutated high grade serious epithelial ovarian, fallopian tube, or peritoneal cancer, who are in response to platinum-based chemotherapy. Over the last two years, several therapeutic indications have been added to the drug label, such as first-line platinum-sensitive BRCA-mutated high grade serious epithelial ovarian, fallopian tube, or peritoneal cancer, germline BRCA1/2-mutated, human epidermal growth factor 2 (HER2-)negative, locally advanced or metastatic breast cancer and BRCA1/2-mutated metastatic castration-resistant prostate cancer, who have progressed following prior therapy. Since olaparib is very expensive, this increase of treatment population will have a significant impact on health care expenditures.

To keep healthcare affordable and accessible for all patients, innovative strategies are warranted to reduce the dose of expensive drugs, without reduction of efficacy. For olaparib, pharmacokinetic (PK) boosting can be applied. PK boosting is the lay term for administering a non-therapeutic active strong inhibitor of a metabolic enzyme, for example the cytochrome p450 enzyme 3A (CYP3A), together with a therapeutic drug that is metabolized by the same enzyme. Boosting thus increases the concentration of the therapeutic drug and allows lower doses to be administered to patients. Hence, coadministration of a reduced dose of olaparib with cobicistat, a non-therapeutic, strong inhibitor of the CYP3A can lead to equivalent exposure to olaparib. Furthermore, inhibition of CYP3A could lead to less PK variability since metabolic capacity is a prominent cause for (intra- and inter-individual) variability in systemic exposure. Predictable olaparib exposure will reduce the number of patients who are unintentionally under- or overtreated. Lastly, tumor tissue itself may express CYP3A as a detoxification or resistance mechanism. Theoretically, PK boosting may also overcome CYP3A-mediated drug resistance.

The purpose of this study is to establish the efficacy, safety and feasibility of co-administering olaparib with the PK booster cobicistat with the aim to implement boosting approach for olaparib in routine practice. The study is subdivided in two parts. In part A of the study the equivalent exposure of boosted low dose olaparib is determined compared to the normal dose. In part B of the study, non-inferiority of the boosted olaparib regimen will be confirmed.


Eligibility criteria: Inclusion Criteria:

* Subjects who are able and willing to provide written informed consent prior to screening;
* Age of 18 years or older;
* Able to measure the outcome of the study in this subject.

Part A:

* Subjects who start or are on treatment with olaparib tablets 300mg twice daily, according to the drug label and physician's discretion;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Part B:

* Subjects who start on treatment with olaparib tablets 300mg twice daily, according to the drug label and physician's discretion;
* Expected to be on olaparib treatment for ≥ 3 months;
* ECOG performance status of 0-3.

Exclusion Criteria:

* Concurrent use of other anti-cancer therapies;
* Concurrent use of potent inducers or inhibitors of the cytochrome p450 enzyme 3A3 (CYP3A4) as assessed with the Dutch drug database "G-Standaard" of the Royal Dutch Pharmacists Association(KNMP);
* Known contra-indications for treatment with cobicistat in line with the summary of product characteristics;
* Subjects with renal insufficiency defined as estimated glomerular filtration rate \< 50 ml/min.

Primary outcomes:
measure: Part A: Olaparib AUC0-12h
timeFrame: 2 weeks
measure: Part B: Progression-free survival (PFS)
timeFrame: 12 months
measure: Part B: Dose reductions
timeFrame: 12 months
Secondary outcomes:
measure: Part A: Inter- and intrapatient variability of AUC0-12h
timeFrame: 2 weeks
measure: Part A: Adverse events
timeFrame: 2 weeks
measure: Part B: Health status
timeFrame: 12 months
measure: Part B: Patient satisfaction
timeFrame: 12 months
measure: Part B: ctDNA
timeFrame: 12 weeks
measure: Part B: Adverse events
timeFrame: 12 months
measure: Part B: Productivity costs
timeFrame: From date of randomization until the date of end-of-treatment, assessed up to 12 months
measure: Part B: Medical consumption
timeFrame: From date of randomization until the date of end-of-treatment, assessed up to 12 months
Other outcomes:
measure: Part A: Patient preference
timeFrame: 2 weeks
measure: Part B: Intratumoral olaparib
timeFrame: At 8 weeks after start treatment and at the moment of progression
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Amsterdam
country: Netherlands
facility: Amsterdam Universitair Medische Centra
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute-Antoni van Leeuwenhoek
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht UMC
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Rotterdam
country: Netherlands
facility: ErasmusMC
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: Radboud University Medical Center
name: Nielka van Erp, prof. PharmD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Overbeek JK, Guchelaar NAD, Mohmaed Ali MI, Ottevanger PB, Bloemendal HJ, Koolen SLW, Mathijssen RHJ, Boere IA, Hamberg P, Huitema ADR, Sonke GS, Opdam FL, Ter Heine R, van Erp NP. Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study). Eur J Cancer. 2023 Nov;194:113346. doi: 10.1016/j.ejca.2023.113346. Epub 2023 Sep 19.