Clinical Trials Register

Summary
EudraCT Number:	2011-005975-17
Sponsor's Protocol Code Number:	MO28113
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-28
Trial results	View 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

Sweden - MPA

A.2

EudraCT number

2011-005975-17

A.3

Full title of the trial

A two-part, randomized Phase III, double-blind, multicenter trial assessing the efficacy and safety of pertuzumab in combination with standard chemotherapy vs. placebo plus standard chemotherapy in women with recurrent platinum resistant epithelial ovarian cancer and low HER3 mRNA expression

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PENELOPE (Pertuzumab in Platinum-resistant low HER3 mRNA epithelial ovarian cancer)

A.4.1

Sponsor's protocol code number

MO28113

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	F. Hoffmann-La Roche Ltd.
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.com

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	Perjeta
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited, UK
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Pertuzumab (rhuMAb 2C4)
D.3.2	Product code	Ro 436-8451/F01
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERTUZUMAB
D.3.9.1	CAS number	380610-27-5
D.3.9.2	Current sponsor code	R04368451
D.3.9.3	Other descriptive name	rhuMAb 2C4
D.3.9.4	EV Substance Code	SUB16455MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Humanized monoclonal antibody

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Women with recurrent platinum-resistant or refractory epithelial ovarian, primary peritoneal, and/or fallopian tube cancer, and low HER3 mRNA expression.

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10066697
E.1.2	Term	Ovarian cancer recurrent
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 1: Safety Run-in Phase
The primary objective for Part 1 of this study is as follows:
-To determine the safety and tolerability of pertuzumab in combination with either topotecan or paclitaxel.

Part 2:
The primary objective for Part 2 of this study is as follows:
-To determine if pertuzumab plus chemotherapy is superior to placebo plus chemotherapy as measured by progression-free survival (PFS) assessed by a blinded independent review committee (IRC).

E.2.2

Secondary objectives of the trial

The secondary objective for Part 1 of this study is as follows:
-To descriptively evaluate the progression-free survival (PFS; assessed by investigator) of pertuzumab in combination with either topotecan or paclitaxel.

The secondary objectives for Part 2 of this study are as follows:
-To determine if pertuzumab plus chemotherapy is superior to placebo plus chemotherapy with respect to:
-Overall survival (OS; key secondary endpoint).
-PFS assessed by investigator.
-Objective response rate (ORR).
-Safety and tolerability including incidence of anti-therapeutic antibodies to pertuzumab.
-Quality of life (QoL).
-PK objectives (see section E.2.3 of this form)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PK substudy. Assuming that topotecan is used in Part 2 of the trial, a subset of sites capable of handling PK sampling and patients who receive topotecan will participate in a PK and drug–drug interaction substudy. Separate Informed Consent Form will be required for participation in the PK substudy (up to approximately 51 patients).
Integrated in updated Protocol Version 3.
Objectives:
-To characterize the PK of pertuzumab in patients with epithelial ovarian, primary peritoneal and/or fallopian tube cancer, and to compare these data with PK data from other clinical trials.
-To characterize the potential of a PK drug-drug interaction between pertuzumab and topotecan.

E.3

Principal inclusion criteria

1. Signed written informed consent approved by the relevant IEC.
2. Female patients aged 18 years or older.
3. Low HER3 mRNA expression levels (concentration ratio equal or lower than 2.81, as assessed by qRT-PCR on a cobas z480 instrument in a central laboratory).
4. Histologically or cytologically confirmed and documented epithelial ovarian, primary peritoneal, and/or fallopian tube cancer that is platinum-resistant or refractory (defined as progression within 6 months from completion of a minimum of 4 platinum therapy cycles or progression during platinum therapy).
5. At least one measurable lesion and/or non measurable lesion according to RECIST version 1.1. The following histological types are eligible:
• Adenocarcinoma not otherwise specified.
• Clear cell adenocarcinoma.
• Endometrioid adenocarcinoma.
• Malignant Brenner's tumor.
• Mixed epithelial carcinoma including malignant mixed Müllerian tumors.
• Mucinous adenocarcinoma.
• Serous adenocarcinoma.
• Transitional cell carcinoma.
• Undifferentiated carcinoma.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
7. LVEF greater than or equal to 50%.
8. Negative serum pregnancy test in women of childbearing potential (WOCBP; premenopausal or less than 12 months of amenorrhea post-menopause, and who have not undergone surgical sterilization).
9. For WOCBP who are sexually active, agreement to use a highly effective, non hormonal form of contraception or two effective forms of non hormonal contraception during and for at least 6 months post-study treatment with IMP or non-IMP (a highly effective non-hormonal form of contraception, such as surgical sterilization, or two effective non-hormonal forms of contraception, such as a barrier method of contraception in conjunction with spermicidal jelly).

E.4

Principal exclusion criteria

1. Non-epithelial tumors.
2. Ovarian tumors with low malignant potential (i.e. borderline tumors).
3. History of other malignancy of prognostic relevance within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma, or tumors with a negligible risk for metastasis or death, such as adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the breast.
4. Serious uncontrolled concomitant disease that would contraindicate the use of any of the investigational drugs used in this study or that would put the patient at high risk for treatment-related complications.
5. Previous treatment with more than 2 chemotherapy regimens, . If a patient has previously been treated with topotecan, paclitaxel, or gemcitabine as second-line therapy, the patient will not be retreated with the same agent.
6. Any prior radiotherapy to the pelvis or abdomen.
7. History or evidence on physical/neurological examination of central nervous system disease unrelated to cancer (e.g. uncontrolled seizures), unless adequately treated with standard medical therapy.
8. Preexisting peripheral neuropathy ≥ CTC Grade 2 (applicable for the paclitaxel cohort only).
9. Inadequate organ function, evidenced by the following laboratory results:
• Absolute neutrophil count <1,500 cells/mm3.
• Platelet count <100,000 cells/mm3.
• Hemoglobin <9 g/dL.
• Total bilirubin greater than 1.5 ×upper limit of normal ([ULN] unless the patient has documented Gilbert’s syndrome).
• Serum alkaline phosphatase, aspartate aminotransferase (AST; SGOT) or alanine aminotransferase (ALT; SGPT) >2.5 × ULN (or > 5 × ULN in the presence of liver metastases)
• Serum creatinine >2.0 mg/dL or >177 μmol/L.
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) >1.5 × ULN (unless on therapeutic anticoagulation).
10. Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident (CVA)/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) any grade, or uncontrollable high risk cardiac arrhythmia (i.e. atrial tachycardia with a heart rate >100/min at rest) or higher grade atrioventricular (AV) block (second degree AC block Type 2 [Mobitz 2] or third degree AV block).
11. Current known infection with HIV or active infection with HBV, or HCV.
12. Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy.
13. Major surgical procedure or significant traumatic injury within 14 days prior to first study drug administration or anticipation of need for major surgery during the course of study treatment.
14. Receipt of i.v. antibiotics for infection within 7 days prior to first study drug administration.
15. Current chronic daily treatment with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
16. Known hypersensitivity to any of the trial drugs or excipients.
17. History of receiving any investigational treatment within 28 days prior to first study drug administration.
18. For Part 2 of the trial: prior enrollment into Part 1 of the trial.
19. Concurrent participation in any therapeutic clinical trial.
20. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.

E.5 End points

E.5.1

Primary end point(s)

Part 1 (safety run-in phase): primary objective will be safety and tolerability (analyses will be descriptive). Descriptive evaluation of PFS as assessed by the investigator.

Part 2
The primary efficacy endpoint is PFS assessed by a blinded IRC.

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1: The main safety and tolerability analyses will be performed when approximately 15 patients have been recruited into each cohort and have received at least 3 cycles of treatment.

Part 2:
The primary analysis for PFS in Part 2 will be event driven and will be performed after 109 PFS events assessed by a blinded IRC have occurred, estimated to be approximately 17 months after randomization of the first patient.

E.5.2

Secondary end point(s)

Part 2:
Efficacy: PFS assessed by the investigator, OS, ORR
Safety:
-Incidence, nature, and severity of all adverse events (AEs), serious adverse events (SAEs), and AEs that caused premature withdrawal from IMP or non-IMP.
-Premature withdrawal from the study and treatment with IMP or non-IMP.
-Cardiac disorders / incidence of congestive heart failure.
-Laboratory test abnormalities.
-LVEF and electrocardiograms (ECGs) over the course of the study.
-Incidence of ATAs to pertuzumab (Part 2 of the trial only).

E.5.2.1

Timepoint(s) of evaluation of this end point

Part 2: A efficacy interim analysis of OS will be performed with the final analysis of PFS (assessed by a blinded IRC). The final analysis of OS will be performed when 129 OS events in Part 2 have occurred.

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Patient-reported outcome measures, biomarkers, assessment of anti-therapeutic antibodies to pertuzumab

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)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Study comprises 2 parts. Part 1: non-randomized, open-l., safety run-in. Part 2 as in section E.8.1

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

European Union

Turkey

E.8.7

Trial has a data monitoring committee

Yes

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

Part 1: see protocol section 3.2
Part 2: see protocol section 3.2

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:

120

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

170

F.4.2.2

In the whole clinical trial

184

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)

See protocol sections 4.3.4 & 4.5.3.
Patients who discontinue both IMP & non-IMP for PD or other reasons will receive treatment according to local standard of care. The Sponsor will provide pertuzumab for patients who are still receiving IMP at the end of the study and who are willing & suitable to enter an extension study. This extension study will continue until pertuzumab is commercially available to participating patients in their countries or Roche ceases producing/studying pertuzumab.

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	AGO Research GmbH
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-07-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-28

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