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 locoregional or metastatic breast carcinoma which has progressed on prior trastuzumab-based therapy.A parallel cohort of 15 patients with HER2-positive, PD-L1 negative disease will be enrolled in the phase II study.
MedDRA version: 18.1Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-004770-10-AT

Lead Sponsor: International Breast Cancer Study Group (IBCSG)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Female

Target Recruitment: 61

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 biopsy from metastatic or unresectable loco-regional lesion.
- trastuzumab resistant disease, defined by:
- progression of disease while on-treatment with trastuzumab
- Recurrence while on adjuvant trastuzumab or within 12 months of completing adjuvant trastuzumab
- Any number of prior lines of anti-HER2 therapy acceptable. Pts for whom treatment with current first-line combination of trastuzumab, pertuzumab and taxanes is not an option can be considered for enrollment.
- If a patient has received a subsequent anti-HER2 therapy, she must also have progressed on the subsequent therapy.
- Presence of at least one measurable lesion (RECIST 1.1)
- LVEF =50%
-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 = 1.5 × 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 (during phase II portion of trial a parallel, secondary cohort of 15 pts with PD-L1 negative disease will be enrolled).
For secondary cohort of 15 pts with PD-L1 negative disease:
Pts previously screened with negative PD-L1 result can be included once AM1 has been approved, provided all eligibility criterias as specified in protocol are met, all tests and scans have been performed within the timelines specified, and biopsy is =1 year from enrollment. Pts must have demonstrated progression on current treatment. Center will need to register the pt again and get a new pt ID.
- 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. For pts who have presented with stage 4 disease de novo, a biopsy taken from the presumed primary breast lesion is acceptable, (provided this was taken =1 year prior to enrollment).
- Patient agrees to submit baseline (pre-treatment) blood and serial plasma for t

Exclusion Criteria

Exclusion criteria for screening:
- Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 therapy.
- 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
- History of or active pneumonitis requiring treatment with steroids
- Active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth
- Leptomeningeal disease
- 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 highly effective contraception during treatment and up to 7 months 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, except alopecia grade 2.
- Human Immunodeficiency Virus (HIV) or positive for Hepatitis B or Hepatitis C.