Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness

Cancer Clinical Trial

— PROACTIVE  

Official title:

Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05078671
• Other study ID #: PROACTIVE
• Status: Recruiting
• Phase: Phase 4
• Start date: December 15, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: June 2024
• Source: Radboud University Medical Center
• Contact: Joanneke K Overbeek, PharmD
• Phone: +31-24-3617744
• Email: joanneke.overbeek[@]radboudumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cancer

Intervention

Drug:
• Olaparib
olaparib treatment
• Cobicistat
Pharmacokinetic booster

Locations

Country	Name	City	State
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	Amsterdam Universitair Medische Centra	Amsterdam
Netherlands	Netherlands Cancer Institute-Antoni van Leeuwenhoek	Amsterdam
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Maastricht UMC	Maastricht
Netherlands	Radboudumc	Nijmegen
Netherlands	ErasmusMC	Rotterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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 (PROA — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Part A: Patient preference	Treatment preference on a 7-point Likert scale.	2 weeks
Other	Part B: Intratumoral olaparib	Intratumoral olaparib concentration in tumor biopsy samples.	At 8 weeks after start treatment and at the moment of progression
Primary	Part A: Olaparib AUC0-12h	The Area-Under-the-Curve (AUC) 0-12h of olaparib.	2 weeks
Primary	Part B: Progression-free survival (PFS)	PFS is defined as time from randomization until the date of either objective radiological disease progression, or biochemical progression combined with clinical progression or death.	12 months
Primary	Part B: Dose reductions	Number of patients who require a dose reduction due to toxicity.	12 months
Secondary	Part A: Inter- and intrapatient variability of AUC0-12h	Inter- and intrapatient variability of AUC0-12h in olaparib as calculated with non-compartmental analysis.	2 weeks
Secondary	Part A: Adverse events	Number of patients with treatment-related adverse events as assessed by CTCAE v5.0.	2 weeks
Secondary	Part B: Health status	Health status as assessed with the EuroQol 5 dimensions with 5 levels questionnaire (EQ-5D-5L).	12 months
Secondary	Part B: Patient satisfaction	Patient satisfaction as assessed with the Cancer Therapy Satisfaction Questionnaire (CTSQ).	12 months
Secondary	Part B: ctDNA	Cell-free tumor nucleic acids (ctDNA) in plasma as pharmacodynamic biomarker.	12 weeks
Secondary	Part B: Adverse events	Number of patients with treatment-related adverse events as assessed by CTCAE v5.0.	12 months
Secondary	Part B: Productivity costs	Productivity costs as assessed by the iMTA Productivity Costs Questionnaire (iPCQ).	From date of randomization until the date of end-of-treatment, assessed up to 12 months
Secondary	Part B: Medical consumption	Medical consumption as assessed by the iMTA Medical Consumption Questionnaire (iMCQ).	From date of randomization until the date of end-of-treatment, assessed up to 12 months