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

• ClinicalTrials.gov Identifier: NCT01684878
• Recruitment Status: Completed
• First Posted: September 13, 2012
• Results First Posted: November 23, 2016
• Last Update Posted: May 23, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 11, 2012
• First Posted Date: September 13, 2012
• Results First Submitted Date: October 3, 2016
• Results First Posted Date: November 23, 2016
• Last Update Posted Date: May 23, 2017
• Actual Study Start Date: October 22, 2012
• Actual Primary Completion Date: January 30, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 13, 2017)

• Part 1: Percentage of Participants With Adverse Events (AEs) [ Time Frame: Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment) ]
  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.
• Part 2: Progression Free Survival (PFS) as Assessed by a Blinded Independent Review Committee (IRC) Including Malignant Bowel Obstruction (MBO) [ Time Frame: Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression) ]
  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.

Original Primary Outcome Measures (submitted: September 12, 2012)

• Part 1: Safety: Incidence of adverse events [ Time Frame: approximately 2.5 years ]
• Part 2: Progression-free survival, tumor assessments according to RECIST version 1.1 or Gynecologic Cancer InterGroup (GCIG) criteria [ Time Frame: approximately 2.5 years ]

Current Secondary Outcome Measures (submitted: April 13, 2017)

• Part 1- Objective Response Rate (ORR) [ Time Frame: Approximately 28 months (assessed at baseline and every 9 weeks from randomization until disease progression) ]
  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.
• Part 2- Objective Response Rate (ORR) [ Time Frame: Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression) ]
  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.
• Part 1: PFS Assessed by the Investigator [ Time Frame: Approximately 28 months (assessed at screening and every 9 weeks from randomization until disease progression) ]
  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.
• Part 2: Progression-free Survival (PFS) Assessed by the Investigator [ Time Frame: Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression) ]
  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.
• Part 2: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire (QLQ) of Core 30 (C30) Score [ Time Frame: Baseline (assessed at baseline and every 9 weeks from randomization until disease progression) ]
  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.
• Part 2: Percentage of Participants With Adverse Events (AEs) [ Time Frame: Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment) ]
  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.
• Part 2: Overall Survival [ Time Frame: Approximately 44 months (assessed at screening and every 9 weeks from randomization until disease progression) ]
  Overall survival was defined as the time from randomization into Part 2 of the trial until death from any cause

Original Secondary Outcome Measures (submitted: September 12, 2012)

• Part 1: Progression-free survival [ Time Frame: approximately 2.5 years ]
• Part 2: Overall survival [ Time Frame: approximately 2.5 years ]
• Part 2: Objective response rate [ Time Frame: approximately 2.5 years ]
• Part 2: Biological progression-free interval [ Time Frame: approximately 2.5 years ]
• Part 2: Safety: Incidence of adverse events [ Time Frame: approximately 2.5 years ]
• Part 2: Quality of life: Quality of Life/Functional Assessment Questionnaires [ Time Frame: approximately 2.5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pertuzumab in Platinum-Resistant Low Human Epidermal Growth Factor Receptor 3 (HER3) Messenger Ribonucleic Acid (mRNA) Epithelial Ovarian Cancer (PENELOPE)
• Official Title: 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
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Ovarian Cancer

Intervention

• 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.
• 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.
• 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.

Study Arms

• 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.
  Interventions:

  • Drug: Paclitaxel (Chemotherapy)
  • Drug: Pertuzumab
  • Drug: Topotecan (Chemotherapy)
• 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.
  Interventions:

  • Drug: Paclitaxel (Chemotherapy)
  • Drug: Pertuzumab
  • Drug: Placebo
• 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.
  Interventions:

  • Drug: Gemcitabine (Chemotherapy)
  • Drug: Paclitaxel (Chemotherapy)
  • Drug: Pertuzumab
  • Drug: Topotecan (Chemotherapy)
• 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.
  Interventions:

  • Drug: Gemcitabine (Chemotherapy)
  • Drug: Paclitaxel (Chemotherapy)
  • Drug: Placebo
  • Drug: Topotecan (Chemotherapy)

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 11, 2015): 208
• Original Estimated Enrollment (submitted: September 12, 2012): 184
• Actual Study Completion Date: April 28, 2016
• Actual Primary Completion Date: January 30, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Denmark, France, Germany, Italy, Netherlands, Norway, Spain, Sweden

Administrative Information

• NCT Number: NCT01684878
• Other Study ID Numbers: MO28113; 2011-005975-17 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: April 2017