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

NCT ID: NCT05078671

Last Updated: 2024-06-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 160 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-15
• Study Completion Date: 2025-12-31

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.

Conditions

Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard olaparib

Olaparib 300mg twice daily

Group Type: ACTIVE_COMPARATOR

Olaparib

Intervention Type: DRUG

olaparib treatment

Boosted olaparib

Olaparib 100mg twice daily + cobicistat 150mg twice daily

Group Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

olaparib treatment

Cobicistat

Intervention Type: DRUG

Pharmacokinetic booster

Interventions

Olaparib

olaparib treatment

Intervention Type: DRUG

Cobicistat

Pharmacokinetic booster

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nielka van Erp, prof. PharmD PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Site Status: RECRUITING

Amsterdam Universitair Medische Centra

Amsterdam, , Netherlands

Site Status: RECRUITING

Netherlands Cancer Institute-Antoni van Leeuwenhoek

Amsterdam, , Netherlands

Site Status: RECRUITING

Amphia Ziekenhuis

Breda, , Netherlands

Site Status: RECRUITING

Universitair Medisch Centrum Groningen

Groningen, , Netherlands

Site Status: RECRUITING

Leiden University Medical Center

Leiden, , Netherlands

Site Status: RECRUITING

Maastricht UMC

Maastricht, , Netherlands

Site Status: RECRUITING

Radboudumc

Nijmegen, , Netherlands

Site Status: RECRUITING

ErasmusMC

Rotterdam, , Netherlands

Site Status: RECRUITING

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Joanneke K Overbeek, PharmD

Role: CONTACT

joanneke.overbeek@radboudumc.nl

+31-24-3617744

Facility Contacts

J. Tol

Role: primary

J.M. Tromp

Role: primary

Frans Opdam, MD, PharmD, PhD

Role: primary

J. Bakker

Role: primary

A.K.L. Reyners

Role: primary

J.R. Kroep

Role: primary

R.I. Lalisang

Role: primary

Nielka van Erp, prof. PharmD PhD

Role: primary

Ron H.J. Mathijssen, prof. MD, PhD

Role: primary

I.O. Baas

Role: primary

References

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.

Reference Type: RESULT

PMID: 37806255 (View on PubMed)

Overbeek JK, Guchelaar NAD, Mohmaed Ali MI, Sark M, Hovenier C, Kievit W, Ligtenberg MJL, Ottevanger PB, Bloemendal HJ, Koolen SLW, Mathijssen RHJ, Boere IA, Huitema ADR, Sonke GS, Opdam FL, Ter Heine R, van Erp NP. Pharmacokinetic boosting of olaparib: Study protocol of a multicentre, open-label, randomised, non-inferiority trial (PROACTIVE-B). Contemp Clin Trials Commun. 2025 Mar 29;45:101477. doi: 10.1016/j.conctc.2025.101477. eCollection 2025 Jun.

Reference Type: DERIVED

PMID: 40248173 (View on PubMed)

Overbeek JK, van Erp NP, Burger DM, den Broeder AA, Koolen SLW, Huitema ADR, Ter Heine R. Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib. Clin Pharmacokinet. 2025 Mar;64(3):425-435. doi: 10.1007/s40262-025-01480-w. Epub 2025 Feb 5.

Reference Type: DERIVED

PMID: 39909979 (View on PubMed)

Other Identifiers

PROACTIVE

Identifier Type: -

Identifier Source: org_study_id