Overview

Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer

Status:
Completed
Trial end date:
2017-08-04
Target enrollment:
0
Participant gender:
Female
Summary
Panacea is a phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab in patients with trastuzumab-resistant, HER2- positive metastatic breast cancers
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
International Breast Cancer Study Group
Collaborator:
Breast International Group
Treatments:
Pembrolizumab
Trastuzumab
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 (immunohistochemistry score 3+) or
ERBB2-amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥ 6) 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. Patients for whom the
treatment with the 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 biopsy 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, indicating the patient has been
informed of and agrees to tissue and blood material use, transfer and handling, 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 biopsies 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

- Hepatic status:

- Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known
Gilbert's syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.

- AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be
≤ 5 × ULN.

- Renal status:

- 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 unless
patient is receiving anticoagulant therapy as long as PT or PTT (partial
thromboplastin time) is within therapeutic range of intended use of anticoagulant.

Inclusion criteria for enrollment:

All inclusion criteria for screening, plus:

- Central lab confirmation on a metastatic biopsy (or biopsy from unresectable
loco-regional disease) of:

- HER2-positivity (immunohistochemistry score 3+) or ERBB2- amplification (Ratio
ERBB2/centromeres ≥2.0 or mean gene copy number ≥ 6),

- Presence of PD-L1 expression assessed by IHC (during the phase II portion of the
trial a parallel, secondary cohort of 15 patients with PD-L1 negative disease
will be enrolled)

- Patient agrees to submit tumor tissue for translational research:

- tissue biopsy from unresectable loco-regional or metastatic disease obtained ≤1
year prior to enrollment or new tissue material from a recently obtained surgical
or diagnostic biopsy. For patients 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).

- if available: FFPE tumor block from primary surgery or diagnostic biopsy.

- if available: pre-treatment fresh frozen tumor biopsy.

- if feasible: FFPE tumor block from post-treatment biopsy will be taken at time of
disease progression or end of all treatment if ended prior to progression. This
re-biopsy is strongly advised.

- if feasible: fresh frozen tumor biopsy from post-treatment biopsy will be taken
at time of disease progression or end of all treatment if ended prior to
progression.

- Patient agrees to submit baseline (pre-treatment) blood and serial plasma for
translational research

- For patient of childbearing potential, negative serum pregnancy test. Pregnancy test
has to be repeated within 72h before treatment start.

- All anti-cancer treatment including endocrine therapy, with the exception of
trastuzumab, must stop 3 weeks prior to first dose of trial treatment.

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) (HIV 1/2 antibodies), or positive for
Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).

- 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 (patients with history of CNS metastases or spinal
cord compression are eligible if they are clinically and radiologically stable for at
least 4 weeks before first dose of investigational product and have not required
high-dose steroid treatment in the last 4 weeks).

- Leptomeningeal disease

- History of clinically significant or uncontrolled cardiac disease, including
congestive heart failure (New York Heart Association functional classification ≥3),
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 including cortico¬steroids.

- 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. Patients with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule. Patients that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the trial. Patients with hypothyroidism stable on hormone replacement or
Sjögren's syndrome will not be excluded from the trial.

- 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.
Acceptable methods are intrauterine devices (without hormones), bilateral tubal
occlusion, vasectomized partner or total abstinence. Oral, injectable, or implant
hormonal contraceptives are not allowed.

- 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:

- All exclusion criteria for screening apply for enrollment as well. Excluded are
especially 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) (HIV 1/2 antibodies), or positive for Hepatitis B
or Hepatitis C.