Clinical Trials Register

Summary
EudraCT Number:	2018-003736-77
Sponsor's Protocol Code Number:	IRFMN-OVA-7814
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-02-20
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

Germany - BfArM

A.2

EudraCT number

2018-003736-77

A.3

Full title of the trial

A multicenter, open-label phase II trial of a new customized dosing (Rational Adjustment of Dose to reduce Adverse Reactions “RADAR” dosing) of niraparib as maintenance therapy in platinum sensitive ovarian, fallopian tube or primary peritoneal recurrent cancer patients.

A.3.1

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

A MULTICENTER TRIAL OF A NEW CUSTOMIZED DOSING (RATIONAL ADJUSTMENT OF DOSE TO REDUCE ADVERSE REACTIONS “RADAR” DOSING) OF NIRAPARIB AS MAINTENANCE THERAPY IN PLATINUM SENSITIVE OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL RECURRENT CANCER PATIENTS

A.3.2

Name or abbreviated title of the trial where available

NEWTON

A.4.1

Sponsor's protocol code number

IRFMN-OVA-7814

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	Istituto di Ricerche Farmacologiche Mario Negri IRCCS
B.1.3.4	Country	Italy
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	GSK
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto di Ricerche Farmacologiche Mario Negri IRCCS
B.5.2	Functional name of contact point	Oncology Department
B.5.3	Address:
B.5.3.1	Street Address	Via Mario Negri 2
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20156
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390239014650
B.5.5	Fax number	00390233200231
B.5.6	E-mail	newton@marionegri.it

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	No
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.3.1	Product name	Niraparib
D.3.2	Product code	Niraparib
D.3.4	Pharmaceutical form	Capsule, hard
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	NIRAPARIB
D.3.9.1	CAS number	1038915-60-4
D.3.9.3	Other descriptive name	NIRAPARIB
D.3.9.4	EV Substance Code	SUB177208
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	100
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, fallopian tube or primary peritoneal recurrent cancer

E.1.1.1

Medical condition in easily understood language

Ovarian, fallopian tube or peritoneal recurrent 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	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10038604
E.1.2	Term	Reproductive system and breast disorders
E.1.2	System Organ Class	10038604 - Reproductive system and breast disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives of the study are:
• to compare the safety profile of niraparib RADAR dosing in terms of occurrence of grade = 3 thrombocytopenia in the first three cycles versus the SmPC approved dosing in patients who either have a baseline body weight =58 and <77kg, or have a baseline body weight =77kg and baseline platelet count <150,000/µL (restricted population);
• to evaluate the improvement in the safety profile of niraparib RADAR dosing in terms of occurrence of grade = 3 thrombocytopenia in the first three cycles.

E.2.2

Secondary objectives of the trial

• to compare the safety profile of RADAR dosing in terms of occurrence of grade = 3 thrombocytopenia in the first six cycles versus the SmPC approved dosing
• to evaluate the improvement in the safety profile of niraparib RADAR dosing in terms of occurrence of grade = 3 thrombocytopenia in the first six cycles
o to compare the efficacy of niraparib RADAR dosing vs. the SmPC dosing (300 mg)
o to compare the safety profile of RADAR dosing compared with the SmPC dosing (300 mg)
o to evaluate the safety of niraparib RADAR
• Compliance: to evaluate patients adherence to the two treatment regimens of niraparib (RADAR and SmPC) under study in terms of average administered dose in the first 6 cycles
• Pharmacokinetic: to assess the minimum level of niraparib at the steady state, i.e. trough level concentration and the peak level at two hours after the daily dose

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. 18 years of age or older, female, any race
2. Histologically diagnosed ovarian cancer, fallopian tube cancer or primary peritoneal cancer
3. High grade serous or high grade endometrioid (grade 2 or 3) histology or known to have BRCAmut (somatic or germline)
4. Has received at least 2 previous lines of platinum-containing therapy (not necessarily consecutive), and has disease that was considered platinum sensitive following the penultimate platinum line (more than 6-months period between penultimate platinum regimen and progression of disease)
5. Has responded to the last platinum line (PR or CR)
6. No more than 8 weeks have elapsed from completion of the last platinum regimen and the patient is still not progressing after response
7. Eastern Cooperative Oncology Group (ECOG) performance status of = 1
8. Adequate bone marrow, kidney and liver function, defined as follows:
a. Absolute neutrophil count = 1,500/µL
b. Platelets = 100,000/µL
c. Hemoglobin = 9 g/dL
d. Serum creatinine = 1.5 x upper limit of normal (ULN) or calculated creatinine clearance = 30 mL/min using the Cockcroft-Gault equation
e. Total bilirubin = 1.5 x ULN (=2.0 in patients with known Gilberts syndrome) OR direct bilirubin = 1 x ULN
f. Aspartate aminotransferase and alanine aminotransferase = 2.5 x ULN unless liver metastases are present, in which case they must be = 5 x ULN
9. Patient receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.
10. Patient must have a negative urine or serum pregnancy test within 7 days
prior to taking study treatment if childbearing potential and agrees to abstain
from activities that could result in pregnancy from screening through 180
days after the last dose of study treatment or use highly effective
contraception throughout the study. Such methods include: combined
(estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-
only hormonal contraception associated with inhibition of ovulation (oral,
injectable, implantable), intrauterine device (IUD), intrauterine hormone-
releasing system (IUS), bilateral tubal occlusion, vasectomized partner. In
case of vomiting and diarrhea patient should use an additional barrier
method. Non-childbearing potential is defined as follows (by other than
medical reasons): ≥45 years of age and has not had menses for >1 year;
patients with amenorrhea for <2 years without history of a hysterectomy and
oophorectomy must have a follicle stimulating hormone value in the
postmenopausal range upon screening evaluation; Post-hysterectomy, post-
bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or
oophorectomy must be confirmed with medical records of the actual
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed
with medical records, otherwise the patient must be willing to use highly
effective contraception throughout the study, starting with the screening
visit through 180 days after the last dose of study treatment.
11. Patient must agree to not breastfeed during the study and for 180 days after the last dose of study treatment.
12. Patient must be able to understand the study procedures and agree to participate in the study by providing written informed consent.
13. Patients must have normal blood pressure or adequately treated and controlled hypertension. (i.e. systolic BP ≤ 140 mmHg and diatolic BP ≤ 90 mmHg)

E.4

Principal exclusion criteria

1. Patient simultaneously enrolled in any interventional clinical trial
2. Invasive cancer other than ovarian cancer within 2 years (except basal or squamous cell carcinoma of the skin that has been definitely treated)
3. Patient with known, symptomatic brain or leptomeningeal metastases
4. Patient with immunocompromised status
5. Patient with known active hepatic disease
6. Prior treatment with a known PARP inhibitor
7. Patient who has had major surgery = 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
8. Patient who has received investigational therapy = 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
9. Patient has had radiation therapy encompassing >20% of the bone marrow within 2 weeks prior to day 1 of protocol therapy
10. Patient has had any radiation therapy within 1 week prior to day 1 of protocol therapy.
11. Patient with known hypersensitivity to niraparib components or excipients.
12. Patient has received a transfusion (platelets or red blood cells) = 4 weeks prior to initiating protocol therapy.
13. Patient has received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
14. Patient has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
15. Patient with any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
16. Patient with a serious, uncontrolled medical disorder. Examples include, but are not limited to, nonmalignant systemic disease, active, uncontrolled infection, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
17. Patient who might be dependent on the sponsor, CRO, site or the
investigator.
18. Patient who has been incarcerated or involuntarily institutionalized
by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG

E.5 End points

E.5.1

Primary end point(s)

Rate of patients experiencing a grade =3 thrombocytopenia during the first three cycles.

E.5.1.1

Timepoint(s) of evaluation of this end point

During the first three cycles

E.5.2

Secondary end point(s)

Rate of patients experiencing a grade =3 thrombocytopenia during the first six cycles

E.5.2.1

Timepoint(s) of evaluation of this end point

During the first six cycles

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

E.6.6

Pharmacokinetic

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

One group wil be randomized and one will be non randomized

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

Same drugs but different dose

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

105

F.4.2.2

In the whole clinical trial

105

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)

Not applicable

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	MaNGO
G.4.3.4	Network Country	Italy
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	NOGGO e.V.

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-06-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-29

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