Pharmacokinetic boosting of olaparib to improve exposure, tolerance and cost-effectiveness (PROACTIVE-study)

INTERVENTION: Trade Name: Tybost Pharmaceutical Form: Tablet INN or Proposed INN: Cobicistat CAS Number: 1004316‐88‐4 Current Sponsor code: cobicistat Other descriptive name: COBICISTAT Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ Trade Name: Lynparza Pharmaceutical Form: Tablet INN or Proposed INN: Olaparib CAS Number: 763113‐22‐0 Current Sponsor code: olaparib Other descriptive name: OLAPARIB Concentration unit: mg milligram(s) Concentration type: range Concentration number: 100‐150 Trade Name: Lynparza Pharmaceutical Form: Tablet INN or Proposed INN: Olaparib CAS Number: 763113‐22‐0 Current Sponsor code: olaparib Other descriptive name: OLAPARIB Concentration unit: mg milligram(s) Concentration type: range Concentration number: 100‐150 CONDITION: Ovarian cancer ; MedDRA version: 20.0 Level: PT Classification code 10033128 Term: Ovarian cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: Secondary end point(s): Part A – proof of concept; 1. Inter‐ and intrapatient variability in olaparib pharmacokinetics with and without cobicistat is calculated using non‐compartmental analysis of PK data;; 2. Adverse events and laboratory safety will be monitored and scored according to the CTCAEv5.0 to describe the safety of boosted olaparib treatment.; ; Part B – clinical evaluation; 1. Health status and satisfaction of patients will be monitored with the CTSQ and EQ‐5D‐5L questionnaires;; 2. ctDNA will be determined from plasma samples;; 3. Adverse events and laboratory safety will be monitored and scored according to the CTCAEv5.0 to describe the safety of boosted olaparib treatment;; 4. Costs for the cost‐effectiveness analysis will be assessed by the iMTA Productivity Cost Quetstionnaire (iPCQ) and iMTA Medical Consumption Questionnaires (iMCQ). Health status will be monitored with the EQ‐5D‐5L questionnaire. ; Timepoint(s) of evaluation of this end point: Part A ‐ proof of concept:; 1. Analysis of olaparib in plasma will be analyzed after data collection.; 2. Safety assessment on every study visit; ; Part B ‐ clinical evaluation; 1. Will be measured at baseline and after 4, 8, 12 weeks of therapy and every 6 months untill progression. ; 2. Plasma samples will be taken at baseline and after 4, 8 and 12 weeks of therapy. ; 3. Safety assessment on every study visit. ; 4. Cost questionnaires on baseline, after 4, 8, 12 weeks of therapy and every 6 months untill progression. PRIMARY OUTCOME: Main Objective: Part A – proof‐of‐concept:; 1. To determine the equivalence of the Area‐Under‐the‐Curve (AUC) of the reduced, boosted dose of olaparib and the regular dose.; Part B – clinical evaluation:; 1. To determine if efficacy by progression‐free survival (PFS) in patients with high grade ovarian cancer receiving olaparib maintenance therapy who are in response following completion of first‐line platinum‐based chemotherapy, treated with the lower equivalent boosted dose of olaparib is non‐inferior to patients treated with the regular dose of olaparib; ; 2. To determine if tolerance by dose reductions due to toxicity in patients treated with the lower equivalent boosted dose of olaparib is non‐inferior to patients treated with the regular dose of olaparib.; Primary end point(s): Part A – proof of concept; 1. AUC0‐12h for the regular and boosted olaparib will be determined using non‐compartmental analysis for the primary objective. Hereto, multiple PK samples will be collected after one week of each treatment regimen at the following times: pre‐dose, ½, 1, 1½, 2, 3, 4, 6, 8 hours after olaparib intake. If possible, additional PK samples will be taken after 10 and 12 hours. ; ; Part B – clinical evaluation; 1. Progression‐free survival (PFS) is defined as the time from randomization until the date of either objective radiological disease progression or biochemical progression combined with clinical progression or death;; o Objective radiological disease progression will be assessed according to RECIST version 1.1;; o Biochemical disease progression will be assessed with serum CA‐125 according to the GCIG criteria;; o Clinical progression will be assessed by treating physician;; 2. The number of patients who require a dose reduction due to toxicity will be registered. ; Secondary Objective: Part A ‐ proof‐of‐concept:; 1. To determine whether boosting reduces the inter‐ and intrapatient PK variability of olaparib;; 2. To describe the safety of boosted olaparib.; Part B ‐ clinical evaluation: ; 1. To investigate whether health status, tolerance and satisfaction of patients treated with the boosted low dose olaparib is comparable to patients treated with the regular dose of olaparib;; 2. To evaluate whether treatment response of boosted versus regular olaparib can be determined with cell‐free tumor nucleic acids (ctDNA) as pharmacodynamic biomarker;; 3. To describe toxicity of the lower equivalent boosted dose of olaparib compared to the regular dose of olaparib;; 4. To compare cost‐effectiveness of the lower equivalent boosted dose of olaparib compared to the regular dose of olaparib. ; Timepoint(s) of evaluation of this end point: Part A – proof of concept; PK assessment will be performed after one week of treatment.; ; Part B ‐ clinical evaluation; PFS and dose reductions will be followed up untill progression on every visit. Hereto, visits will be at baseline, after 4, 8, 12 weeks of therapy and every 3 months thereafter. ; ; ; INCLUSION CRITERIA: Part A – proof of concept • Subjects who start or are on treatment with olaparib tablets 300mg BID, according to the drug label and physician’s discretion; • 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 (e.g. patient availability; willing and being able to undergo repeated plasma sample collection); • Eastern Cooperative Oncology Group (ECOG) performance status of 0‐1. Part B – clinical evaluation • Subjects who start on treatment with olaparib tablets 300mg BID, according to the drug label and physician’s discretion; • 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 (e.g. patient availability; willing and being able to undergo sample collection for PK and PD purposes);

Epistemonikos ID: 7e66cc402f98f3d0a1a1ec10de15897e86036a4d
First added on: Aug 25, 2024