A multicenter randomized phase II study to compare the combination trastuzumab and capecitabine, with or without pertuzumab, in patients with HER2-positive metastatic breast cancer that have progressed after one line of trastuzumab-based therapy in the metastatic setting (PHEREXA)

Phase 1

• Conditions: HER2 positive metastatic breast cancer which has progressed after one line of trastuzumab-based therapy in the metastatic setting; MedDRA version: 9.1Level: LLTClassification code 10065430Term: HER-2 positive breast cancer

• Registration Number: EUCTR2008-006801-17-FR
• Lead Sponsor: F. Hoffmann-La Roche Ltd.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2009-09-07
• Last Update Posted: 2 October 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Female
• Target Recruitment: 450

Inclusion Criteria

Disease-Specific:
1. Pathologically confirmed breast cancer and documented metastatic disease.
2. HER2-positive (FISH/CISH-positive and/or IHC 3+) MBC confirmed by a Sponsor-designated central laboratory. It is recommended that a formalin-fixed paraffin embedded (FFPE) tumor tissue block from the primary tumor (and/or metastatic site, if primary tumor not available) or a minimum of 6 unstained and freshly cut slides required for HER2 testing are provided. For subsequent biomarker investigations only in consenting patients, it is advised that a maximum of 25 slides from the tumor tissue material will be provided.
3. Disease progression during or following a trastuzumab-based treatment for first-line metastatic breast cancer.
4. Trastuzumab must have been part of the last prior treatment regimen.
5. Prior treatment with a taxane-containing regimen.
General:
6. Female patients, age =18 years.
7. LVEF = 50% at baseline (assessed within 42 days prior to randomization) as determined by either 2D echocardiogram (ECHO) or MUGA (ECHO is the preferred method). If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study, and to the extent possible, be obtained at the same institution.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. For women of childbearing potential, agreement to use highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner. Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study treatment.
10. Written and signed informed consent (approved by the Independent Ethics Committee) obtained prior to beginning any protocol-specific procedures.

Are the trial subjects under 18? no
Number of subjects for this age range:
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

Exclusion Criteria

Cancer-Related:
1. Prior therapy with pertuzumab or capecitabine.
2. Concurrent immunotherapy or anticancer hormonal therapy.
3. Existing acute reversible effects of prior treatment. This generally means at least 3 weeks should have elapsed since prior chemotherapy and at least 4 weeks since prior (radical) radiotherapy or major surgery with full recovery.
4. History of another malignancy which could affect compliance with the protocol or interpretation of results. Patients treated with curative intent and disease-free for at least 5 years are generally eligible, as are patients treated curatively for carcinoma in situ of the cervix or non-melanomatous skin cancer.
5. CNS metastases which are not well controlled. Eligible patients must be asymptomatic, can not be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment. Note: CT or MRI scan of the brain is mandatory (within 4 weeks prior to randomization) in case of clinical suspicion of CNS metastases.
6. History of exposure to at least one of the following cumulative doses of anthracyclines

Hematological, Biochemical and Organ Function:
7. Current uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mmHg) or unstable angina.
8. History of CHF of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and/or paroxysmal supraventricular tachycardia).
9. History of myocardial infarction within 6 months prior to randomization.
10. History of LVEF decline to below 50% during or after prior trastuzumab therapy or other cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab.
11. Current dyspnoea at rest requiring supportive oxygen therapy or with significant pleural effusions.

General Exclusion Criteria
12. Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization.
13. Current severe, uncontrolled systemic disease (e.g. clinical significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures).
14. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or place the patient at high risk from treatment complications.
15. Patients with insulin-dependent diabetes
16. Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start without full recovery, or anticipation of the need for major surgery during the course of study treatment.
17. Pregnant or lactating females.
18. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study screening.
19. Current known infection with HIV, HBV, or HCV.
20. Active infection requiring antibiotics within 14 days prior to randomization.
21. Current chronic daily treatment with corticosteroids (dose of >10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
22. Known hypersensitivity to any of the study drugs. History of severe and unexpected reactions to fluoropyrimidine therapy.
23. Malabsorption syndrome, disease significantly affecting gastrointestinal function,

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Secondary Objective: To evaluate: <br>-Overall survival (OS)<br>-PFS based on tumor assessments by the Investigators<br>-Time to progression (TTP) based on IRF assessment<br>-Time to treatment failure (TTF) based on IRF assessment<br>-Overall objective response rate (ORR) clinical benefit rate (CBR), based on Investigator and IRF assessments<br>-Duration of objective response (DR) based on IRF assessment<br>-Safety and tolerability of trastuzumab plus capecitabine in combination with pertuzumab <br>-Correlation between biomarkers from tumor tissues and clinical outcomes<br>;Main Objective: To compare progression-free survival (PFS) between the two treatment arms based on assessments by an independent review facility (IRF).<br>;Primary end point(s): The primary endpoint is PFS based on IRF evaluation. PFS is defined as the time from randomization to the first documented disease progression, (PD) as determined by IRF using RECIST version 1.0, or death from any cause, whichever occurs first.