Clinical Trials Register

Summary
EudraCT Number:	2021-004032-28
Sponsor's Protocol Code Number:	112415
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-08-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2021-004032-28

A.3

Full title of the trial

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

Farmacokinetisch boosten van olaparib om blootstelling, tolerantie en kosten-effectiviteit te verbeteren (PROACTIVE-studie)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A lower dose olaparib (Lynparza®), combined with a drug which inhibits olaparib degradation, to increase tolerability and decrease the price of the treatment with olaparib

Een lagere dosis olaparib (Lynparza®), gecombineerd met een medicijn dat de afbraak van olaparib remt, zodat patiënten het geneesmiddel beter verdragen en de prijs van de behandeling met olaparib omlaag kan.

A.3.2

Name or abbreviated title of the trial where available

PROACTIVE

A.4.1

Sponsor's protocol code number

112415

A.5.4

Other Identifiers

Name:

PaNaMa

Number:

112415

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Radboud University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Radboud University Medical Center
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Radboud University Medical Center
B.5.2	Functional name of contact point	Nielka van Erp
B.5.3	Address:
B.5.3.1	Street Address	Geert Grooteplein-Zuid 10
B.5.3.2	Town/ city	Nijmegen
B.5.3.3	Post code	6525 GA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31243617744
B.5.5	Fax number	+31243668755
B.5.6	E-mail	nielka.vanerp@radboudumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tybost
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Ireland UC
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cobicistat
D.3.9.1	CAS number	1004316-88-4
D.3.9.2	Current sponsor code	cobicistat
D.3.9.3	Other descriptive name	COBICISTAT
D.3.9.4	EV Substance Code	SUB33760
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Lynparza
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Olaparib
D.3.9.1	CAS number	763113-22-0
D.3.9.2	Current sponsor code	olaparib
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Lynparza
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Olaparib
D.3.9.1	CAS number	763113-22-0
D.3.9.2	Current sponsor code	olaparib
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ovarian cancer

E.1.1.1

Medical condition in easily understood language

Ovarian cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10033128
E.1.2	Term	Ovarian cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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, 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);
• Expected to be on olaparib treatment for ≥ 3 months;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

E.4

Principal exclusion criteria

Part A + B
• Concurrent use of other anti-cancer therapies;
• Concurrent use of potent inducers or inhibitors of CYP3A4 as assessed with the KNMP “G-standaard”;
• Known contra-indications for treatment with cobicistat in line with the summary of product characteristics;

E.5 End points

E.5.1

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.

E.5.1.1

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.

E.5.2

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.

E.5.2.1

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 6 and 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 6 and 12 weeks of therapy and every 6 months untill progression.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Part A is cross over. Part B is parallel

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Olaparib 300mg BID

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

128

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

160

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None, patients will follow routine clinical care after trial completion

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-08-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-24

P. End of Trial
P.	End of Trial Status	Ongoing

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