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

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.

Study Overview

• Status: Recruiting
• Conditions: Cancer
• Intervention / Treatment: Drug: Olaparib; Drug: Cobicistat

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Joanneke K Overbeek, PharmD; Phone Number: +31-24-3617744; Email: joanneke.overbeek@radboudumc.nl

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Recruiting
    • Jeroen Bosch Ziekenhuis
    • Contact: J. Tol
  • Amsterdam, Netherlands
    • Recruiting
    • Netherlands Cancer Institute-Antoni van Leeuwenhoek
    • Contact: Frans Opdam, MD, PharmD, PhD
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam Universitair Medische Centra
    • Contact: J.M. Tromp
  • Breda, Netherlands
    • Recruiting
    • Amphia Ziekenhuis
    • Contact: J. Bakker
  • Groningen, Netherlands
    • Recruiting
    • Universitair Medisch Centrum Groningen
    • Contact: A.K.L. Reyners
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: J.R. Kroep
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht UMC
    • Contact: R.I. Lalisang
  • Nijmegen, Netherlands
    • Recruiting
    • Radboudumc
    • Contact: Nielka van Erp, prof. PharmD PhD
  • Rotterdam, Netherlands
    • Recruiting
    • ErasmusMC
    • Contact: Ron H.J. Mathijssen, prof. MD, PhD
  • Utrecht, Netherlands
    • Recruiting
    • Universitair Medisch Centrum Utrecht
    • Contact: I.O. Baas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard olaparib; Olaparib 300mg twice daily	Drug: Olaparib; olaparib treatment
Experimental: Boosted olaparib; Olaparib 100mg twice daily + cobicistat 150mg twice daily	Drug: Olaparib; olaparib treatment; Drug: Cobicistat; Pharmacokinetic booster

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Olaparib AUC0-12h	The Area-Under-the-Curve (AUC) 0-12h of olaparib.	2 weeks
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
Part B: Dose reductions	Number of patients who require a dose reduction due to toxicity.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Part A: Adverse events	Number of patients with treatment-related adverse events as assessed by CTCAE v5.0.	2 weeks
Part B: Health status	Health status as assessed with the EuroQol 5 dimensions with 5 levels questionnaire (EQ-5D-5L).	12 months
Part B: Patient satisfaction	Patient satisfaction as assessed with the Cancer Therapy Satisfaction Questionnaire (CTSQ).	12 months
Part B: ctDNA	Cell-free tumor nucleic acids (ctDNA) in plasma as pharmacodynamic biomarker.	12 weeks
Part B: Adverse events	Number of patients with treatment-related adverse events as assessed by CTCAE v5.0.	12 months
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Patient preference	Treatment preference on a 7-point Likert scale.	2 weeks
Part B: Intratumoral olaparib	Intratumoral olaparib concentration in tumor biopsy samples.	At 8 weeks after start treatment and at the moment of progression

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Nielka van Erp, prof. PharmD PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2021
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: September 22, 2021
• First Submitted That Met QC Criteria: October 4, 2021
• First Posted (Actual): October 14, 2021

Study Record Updates

• Last Update Posted (Actual): June 12, 2024
• Last Update Submitted That Met QC Criteria: June 10, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: olaparib; pharmacokinetic enhancement
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cobicistat; Olaparib
• Other Study ID Numbers: PROACTIVE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No