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

Study Overview
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Brief Summary
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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.

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

Conditions
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Cancer

Intervention / Treatment
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* Drug: Olaparib
* Drug: Cobicistat


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part A: cross-over normal olaparib versus boosted olaparib. Part B: normal olaparib versus boosted olaparib in two patient groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard olaparib<br>Olaparib 300mg twice daily | Drug: Olaparib<br>* olaparib treatment<br>|
| Experimental: Boosted olaparib<br>Olaparib 100mg twice daily + cobicistat 150mg twice daily | Drug: Olaparib<br>* olaparib treatment<br>Drug: Cobicistat<br>* Pharmacokinetic booster<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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olaparib, pharmacokinetic enhancement