A phase Ib/II trial evaluating the efficacy of the antibody MK-3475 and standard therapy trastuzumab in patients with trastuzumab-resistant, HER2-positive advanced breast cancers

Phase 1

• Conditions: Patients with HER2-positive, PD-L1 expressing, unresectable locoregionalor metastatic breast carcinoma which has progressed on priortrastuzumab-based therapy; MedDRA version: 17.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2013-004770-10-IT
• Lead Sponsor: International Breast Cancer Study Group (IBCSG)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-09-02
• Study Completion: 2017-08-04
• Last Update Posted: 23 November 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Female
• Target Recruitment: 58

Inclusion Criteria

Inclusion criteria for screening:
- Female gender
- Age = 18 years
- Histologically confirmed breast adenocarcinoma that is unresectable loco-regional, or metastatic.
- Locally confirmed HER2-positivity or ERBB2-amplification of primary tumor or of sample from metastatic or locally advanced biopsy.
- progression of disease while on-treatment with trastuzumab and by radiological or clinical assessment, with the presence of at least one measurable lesion as defined by RECIST 1.1.
- If a patient has received a subsequent anti-HER2 therapy, she must also have progressed on the subsequent therapy.
- LVEF =55%
-Patient agrees to submit an FFPE tumor sample for central
confirmation of HER2 positivity and central assessment of PD-L1
status.
- Written Informed Consent (IC) for screening procedures and trial participation must be signed and dated by the patient and the Investigator prior to screening.
- Written consent to biological material submission, must be signed and dated by the patient and the investigator prior to any procedures specific for this trial,including consent to translational research on FFPE and fresh frozen tumor samples in case the patient is enrolled into the trial.
- The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
- Life expectancy >3 months.
- Hematopoietic status:
- Absolute neutrophil count = 1.0 × 109/L,
- Platelet count = 100 × 109/L,
- Hemoglobin = 9 g/dL
- Serum total bilirubin = 1.5 × upper limit of normal (ULN).
- AST and ALT = 2.5 × ULN; if the patient has liver metastases, ALT and AST must be
= 5 × ULN.
- Creatinine = 1.5 ×ULN or creatinine clearance > 60 ml/min
- Proteinuria <1 g/day
- International Normalized Ratio (INR) or Prothrombin Time (PT) =1.5 × ULN

Inclusion criteria for enrollment:
- Central lab confirmation on a metastatic sample of HER2-positivity and PD-L1 expression
- Patient agrees to submit tumor tissue for translational research:
- tissue sample from unresectable loco-regional or metastatic disease
obtained =1 year prior to enrollment or new tissue material from a
recently obtained surgical or diagnostic core biopsy.
- Patient agrees to submit baseline (pre-treatment) blood and serial
plasma for translational research?
- For patient of childbearing potential, negative serum pregnancy test. ?
- All anti-cancer treatment including endocrine therapy, with the
exception of trastuzumab, must stop 3 weeks prior to first dose of trial treatment.
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 23
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 23

Exclusion Criteria

Exclusion criteria for screening:
- Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 therapy.
- More than three lines of anti-HER2 treatment in the metastatic setting
- No FFPE material to centrally assess HER2-positivity and PD-L1 expression.
- Known Human Immunodeficiency Virus (HIV), or positive for Hepatitis B or C
- Interstitial lung disease
- Active central nervous system metastases, as indicated by clinical
symptoms, cerebral edema, and/or progressive growth
- History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction or ventricular arrhythmia.
- Previous severe hypersensitivity reaction to treatment with another monoclonal
antibody
- Active infection requiring systemic therapy
- Chronic systemic therapy with immunosuppressive agents incl. corticosteroids
- Concurrent disease or condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient’s safety
- Known history of uncontrolled hypertension (= 180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen.
- Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent.
- Treatment with an investigational agent in the 4 weeks before enrollment.
- Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
- Chemotherapy, radioactive therapy, and/or biological cancer therapy within 3 weeks prior to the first trial dose and has not recovered to CTCAE v.4 grade 1 or better from adverse events.
- Pregnant or lactating women; lactation has to stop before enrollment.
- The patient of childbearing potential who is unwilling to use effective contraception during treatment and up to 120 days after stop of trial treatment.
-Unresolved or unstable, serious adverse events from prior administration of another investigational drug.
- Active or uncontrolled infection CTCAE v.4 grade 2 or higher.
- Live vaccines within 30 days prior to the first dose of trial therapy and during trial treatment.

Exclusion criteria for enrollment:
- patients who have received any of the treatments below:
? -Live vaccines within 30 days prior to the first dose of trial therapy
and during trial treatment.
? - History of CNS metastases or spinal cord compression if they have
not been clinically stable for at least 4 weeks before first dose of
investigational product and require high-dose steroid treatment.
- Treatment with an investigational agent in the 4 weeks before enrollment.
- Patient has not recovered to CTCAE v.4 grade 1 or better from
adverse events of prior therapy.

Study & Design

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