Pertuzumab in Platinum-Resistant Low Human Epidermal Growth Factor Receptor 3 (HER3) Messenger Ribonucleic Acid (mRNA) Epithelial Ovarian Cancer (PENELOPE)

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

This two-part, multicenter study will evaluate the safety, tolerability and efficacy of pertuzumab in combination with standard chemotherapy in women with recurrent platinum-resistant epithelial ovarian cancer. In the non-randomized Part 1 safety run-in, participants will receive pertuzumab plus either topotecan or paclitaxel. In the randomized, double-blind Part 2 of the study, participants will receive either pertuzumab or placebo in combination with chemotherapy (topotecan, paclitaxel, or gemcitabine).

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Paclitaxel (Chemotherapy); Drug: Pertuzumab; Drug: Topotecan (Chemotherapy); Drug: Placebo; Drug: Gemcitabine (Chemotherapy)

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Tiroler Landeskrankenanstalten Ges.M.B.H.; Abt. Für Gynäkologie
  • Wien, Austria, 1090
    • Medizinische Universität Wien; Univ.Klinik für Frauenheilkunde - Klinik für Gynäkologie
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Denmark
  • Herlev, Denmark, 2730
    • Herlev Hospital; Onkologisk afdeling
  • København Ø, Denmark, 2100
    • Rigshospitalet, Onkologisk Klinik
• France
  • Bordeaux, France, 33076
    • Institut Bergonie; Oncologie
  • Caen, France, 14076
    • Centre Francois Baclesse; Oncologie
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc; Oncologie 3
  • Montpellier cedex 5, France, 34298
    • CRLCC Val dAurelle Paul Lam
  • Paris, France, 75970
    • Hopital Tenon; Oncologie Radiotherapie
  • Pierre Benite, France, 69310
    • Ch Lyon Sud; Chir Onc Gyne Sct Jules Courmont
  • Plerin, France, 22190
    • Clinique Armoricaine Radiologie; Hopital de Jour
  • Saint Herblain, France, 44805
    • Ico Rene Gauducheau; Oncologie
  • Vandoeuvre Les Nancy, France, 54511
    • Centre Alexis Vautrin; Oncologie Medicale
  • Villejuif, France, 94800
    • Institut Gustave Roussy; Oncologie Medicale
• Germany
  • Dresden, Germany, 01307
    • Universitätsklinikum "Carl Gustav Carus"; Frauenheilkunde und Geburtshilfe
  • Düsseldorf, Germany, 40217
    • Evangelischen Krankenhauses Düsseldorf; Frauenklinik
  • Essen, Germany, 45122
    • Universitätsklinikum Essen; Zentrum Für Frauenheilkunde
  • Essen, Germany, 45136
    • Kliniken Essen-Mitte Evang. Huyssens-Stiftung, Klinik für Gynäkologie und gynäkologische Onkologie
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg; Frauenklinik
  • Greifswald, Germany, 17475
    • Universitätsklinikum Greifswald; Klinik für Frauenheilkunde und Brustzentrum
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf (UKE); Klinik und Poliklinik für Gynäkologie
  • Hannover, Germany, 30177
    • Gynaekologisch-Onkologische Schwerpunktpraxis Prof. Dr. med. Lueck, Dr. Schrader und Dr. Noeding
  • Heidelberg, Germany, 69120
    • Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg
  • Kiel, Germany, 24105
    • UNI-Klinikum Campus Kiel Klinik f.Gynäkologie u.Geburtshilfe
  • Koeln, Germany, 50935
    • St. Elisabeth Krankenhaus Köln GmbH; Gynäkologie und Geburtshilfe
  • Konstanz, Germany, 78464
    • Klinikum Konstanz, Frauenklinik
  • München, Germany, 81675
    • Klinikum rechts der Isar der TU München; Frauenklinik & Poliklinik
  • Offenbach, Germany, 63069
    • Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe
  • Ravensburg, Germany, 88212
    • Hämatologisch/Onkologische Praxis Dr. Herbrick - Zipp/Prof. Dr. Decker, Studienzentrum
  • Rostock, Germany, 18059
    • Universitätsfrauen- und Poliklinik am Klinikum Suedstadt
  • Tübingen, Germany, 72076
    • Universitätsklinik Tübingen; Frauenklinik
  • Ulm, Germany, 89075
    • Universitätsklinikum Ulm Am Michelsberg; Frauenklinik
  • Wiesbaden, Germany, 65199
    • HELIOS Dr. Horst Schmidt Kliniken Wiesbaden; Klinik für Gynäkologie und gynäkologische Onkologie
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Istituto Tumori Napoli;Unità Operativa Oncologia Medica Uro-Ginecologica
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Istituto Regina Elena; Oncologia Medica A
  • Liguria
    • Genova, Liguria, Italy, 16128
      • Ente Ospedaliero Ospedali Galliera; S.C. Oncologia Medica
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • A.O.Spedali Civili; Ostetricia e Ginecologia
    • Milano, Lombardia, Italy, 20141
      • Istituto Europeo di Oncologia
    • Milano, Lombardia, Italy, 20133
      • Istituto Nazionale dei Tumori; Divisione Oncologia Chirurgica e Ginecologica
  • Toscana
    • Pisa, Toscana, Italy, 56126
      • A.O.U Pisana; Dipartimento di Ginecologia Oncologica
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Antoni van Leeuwenhoek Ziekenhuis
  • Groningen, Netherlands, 9713 GZ
    • Academ Ziekenhuis Groningen; Medical Oncology
  • Leiden, Netherlands, 2333 ZA
    • Academisch Ziekenhuis Leiden; Clinical Oncology
  • Nijmegen, Netherlands, 6525 GA
    • UMC St Radboud
• Norway
  • Oslo, Norway, 0379
    • The Norvegian Radium Hospital Montebello; Dept of Oncology
• Spain
  • Barcelona, Spain, 08035
    • Hospital Univ Vall d'Hebron; Servicio de Oncologia
  • Barcelona, Spain, 08907
    • Hospital Duran i Reynals; Oncologia
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial; Servicio de Hematología y Oncología
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau; Servicio de Oncologia
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofia; Servicio de Oncologia
  • Girona, Spain, 17007
    • Hospital Universitari de Girona Dr. Josep Trueta; Servicio de Oncologia
  • Lerida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre; Servicio de Oncologia
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon; Servicio de Oncologia
  • Madrid, Spain, 28033
    • Centro Oncologico MD Anderson Internacional; Servicio de Oncologia
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz; Servicio de Oncologia
  • Madrid, Spain, 28050
    • Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
  • Malaga, Spain, 29010
    • Hospital Regional Universitario Carlos Haya; Servicio de Oncologia
  • Murcia, Spain, 30120
    • Hospital Universitario Virgen de Arrixaca; Servicio de Oncologia
  • Valencia, Spain, 46009
    • Instituto Valenciano Oncologia; Oncologia Medica
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe; Servicio de Oncologia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet; Servicio Oncologia
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Corporacio Sanitaria Parc Tauli; Servicio de Oncologia
  • Islas Baleares
    • Palma de Mallorca, Islas Baleares, Spain, 07198
      • Hospital Son Llatzer; Servicio de Oncologia
• Sweden
  • Linkoeping, Sweden, 58185
    • Universitetssjukhuset; Onkologkliniken
  • Lund, Sweden, 22185
    • Skånes University Hospital, Skånes Department of Onclology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Histologically or cytologically confirmed epithelial ovarian, primary peritoneal, and/or fallopian tube cancer that is platinum-resistant or refractory
• Low Human epidermal growth factor receptor (HER) 3 messenger ribonucleic acid (mRNA) expression
• At least one measurable and/or non-measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version (V) 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Left ventricular ejection fraction (LVEF) greater than or equal to (>/=) 50 percent (%)
• Negative serum pregnancy test in women of childbearing potential
• Women of childbearing potential must agree to use effective contraception as defined by protocol during and for at least 6 months post study treatment

Exclusion Criteria:

• Non-epithelial tumors
• Ovarian tumors with low malignant potential (borderline tumors)
• 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 cervix or carcinoma in situ of the breast
• Previous treatment with more than 2 chemotherapy regimens
• Any prior radiotherapy to the pelvis or abdomen
• History or evidence on physical/neurological examination of central nervous system disease unrelated to cancer (uncontrolled seizures), unless adequately treated with standard medical therapy
• Pre-existing peripheral neuropathy >/= common toxicity criteria (CTC) grade 2 (applicable for paclitaxel cohort only)
• Inadequate organ function
• Uncontrolled hypertension or clinically significant cardiovascular disease
• Current known infection with human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV)
• Current chronic daily treatment with corticosteroids (>/= 10 mg per day of methylprednisolone or equivalent), excluding inhaled steroids
• History of receiving any investigational treatment within 28 days prior to first study drug administration
• For Part 2 of the trial: prior enrollment into Part 1 of the trial
• Concurrent participation in any therapeutic clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Pertuzumab + Topotecan; Participants received pertuzumab and topotecan in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death.	Drug: Paclitaxel (Chemotherapy); Participants administered paclitaxel at a dosage of 80 mg/m^2 as 1 hour IV infusion on Days 1, 8 and 15 every 3 weeks.; Drug: Pertuzumab; Participants administered pertuzumab 840 milligrams (mg) IV infusion on Day 1 of the first treatment cycle as a loading dose, followed by 420 mg on Day 1 of each subsequent 3 weekly cycle.; Drug: Topotecan (Chemotherapy); Participants administered topotecan at a dosage of 1.25 mg/m^2 as a 30 minute IV infusion daily on Days 1 to 5 every 3 weeks.
Experimental: Part 1: Pertuzumab + Paclitaxel; Participants received pertuzumab and paclitaxel in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death.	Drug: Paclitaxel (Chemotherapy); Participants administered paclitaxel at a dosage of 80 mg/m^2 as 1 hour IV infusion on Days 1, 8 and 15 every 3 weeks.; Drug: Pertuzumab; Participants administered pertuzumab 840 milligrams (mg) IV infusion on Day 1 of the first treatment cycle as a loading dose, followed by 420 mg on Day 1 of each subsequent 3 weekly cycle.; Drug: Placebo; Participants administered pertuzumab matching placebo IV infusion on Day 1 of each 3 weekly cycle.
Experimental: Part 2: Pertuzumab+Chemotherapy; Participants received pertuzumab and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigators discretion.	Drug: Paclitaxel (Chemotherapy); Participants administered paclitaxel at a dosage of 80 mg/m^2 as 1 hour IV infusion on Days 1, 8 and 15 every 3 weeks.; Drug: Pertuzumab; Participants administered pertuzumab 840 milligrams (mg) IV infusion on Day 1 of the first treatment cycle as a loading dose, followed by 420 mg on Day 1 of each subsequent 3 weekly cycle.; Drug: Topotecan (Chemotherapy); Participants administered topotecan at a dosage of 1.25 mg/m^2 as a 30 minute IV infusion daily on Days 1 to 5 every 3 weeks.; Drug: Gemcitabine (Chemotherapy); Participants administered gemcitabine at a dosage of 1000 milligrams per square meter (mg/m^2) intravenous (IV) infusion on Days 1 and 8 every 3 weeks.
Placebo Comparator: Part 2: Placebo+Chemotherapy; Participants received pertuzumab matching placebo and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigators discretion.	Drug: Paclitaxel (Chemotherapy); Participants administered paclitaxel at a dosage of 80 mg/m^2 as 1 hour IV infusion on Days 1, 8 and 15 every 3 weeks.; Drug: Topotecan (Chemotherapy); Participants administered topotecan at a dosage of 1.25 mg/m^2 as a 30 minute IV infusion daily on Days 1 to 5 every 3 weeks.; Drug: Placebo; Participants administered pertuzumab matching placebo IV infusion on Day 1 of each 3 weekly cycle.; Drug: Gemcitabine (Chemotherapy); Participants administered gemcitabine at a dosage of 1000 milligrams per square meter (mg/m^2) intravenous (IV) infusion on Days 1 and 8 every 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Percentage of Participants With Adverse Events (AEs)	An AE can be any unfavorable and unintended sign (including an abnormality laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment)
Part 2: Progression Free Survival (PFS) as Assessed by a Blinded Independent Review Committee (IRC) Including Malignant Bowel Obstruction (MBO)	PFS (IRC-Assessed) was defined as the time from randomization into Part 2 of the trial until progressive disease (PD), MBO or death from any cause, whichever occurred first per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions.	Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1- Objective Response Rate (ORR)	ORR was defined as the number of participants with best overall response (BOR) of complete response (CR) or partial response (PR) recorded from the start of treatment, until the end of treatment. BOR documented as confirmed CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeter (mm). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Approximately 28 months (assessed at baseline and every 9 weeks from randomization until disease progression)
Part 2- Objective Response Rate (ORR)	ORR was defined as the number of participants with BOR of CR or PR recorded from the start of treatment, until the end of treatment. BOR documented as confirmed CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeter (mm). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression)
Part 1: PFS Assessed by the Investigator	PFS as assessed by Investigator was defined as the time from first dose of pertuzumab or chemotherapy in Part 1 of the trial, until disease progression according to RECIST version 1.1, symptomatic deterioration or death from any cause, whichever occurs first. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Participants were censored at the last tumor assessment. Participants who have no tumor assessments after baseline and who were still alive will be censored at 1 day.	Approximately 28 months (assessed at screening and every 9 weeks from randomization until disease progression)
Part 2: Progression-free Survival (PFS) Assessed by the Investigator	PFS (Investigator-assessed) is defined as the time from randomization, until disease progression according to RECIST v1.1 including death or MBO, whichever occurs first. Censoring is based on the last tumor assessment. If no tumor assessment post baseline, then censoring is at day 1. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions.	Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression)
Part 2: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire (QLQ) of Core 30 (C30) Score	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores averaged, transformed to 0-100 scale; for functional scores, a higher score represents a better level of functioning. For symptom scores, a higher score represents a more severe level of symptoms. For the global health status scores, a higher score represents a better quality of life.	Baseline (assessed at baseline and every 9 weeks from randomization until disease progression)
Part 2: Percentage of Participants With Adverse Events (AEs)	An AE can be any unfavorable and unintended sign (including an abnormality laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment)
Part 2: Overall Survival	Overall survival was defined as the time from randomization into Part 2 of the trial until death from any cause	Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Lorusso D, Hilpert F, Gonzalez Martin A, Rau J, Ottevanger P, Greimel E, Luck HJ, Selle F, Colombo N, Kroep JR, Mirza MR, Berger R, Pardo B, Grischke EM, Berton-Rigaud D, Martinez-Garcia J, Vergote I, Redondo A, Cardona A, Bastiere-Truchot L, du Bois A, Kurzeder C; PENELOPE trial investigators. Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer. Int J Gynecol Cancer. 2019 Sep;29(7):1141-1147. doi: 10.1136/ijgc-2019-000370. Epub 2019 Aug 15.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2012
• Primary Completion (Actual): January 30, 2015
• Study Completion (Actual): April 28, 2016

Study Registration Dates

• First Submitted: September 11, 2012
• First Submitted That Met QC Criteria: September 12, 2012
• First Posted (Estimate): September 13, 2012

Study Record Updates

• Last Update Posted (Actual): May 23, 2017
• Last Update Submitted That Met QC Criteria: April 13, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Gemcitabine; Paclitaxel; Topotecan; Pertuzumab
• Other Study ID Numbers: MO28113; 2011-005975-17 (EudraCT Number)