| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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. |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with fast growing breast cancer that is locally advanced or has spread to other parts of the body (metastatic) and has progressed on prior
trastuzumab-based therapy
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of this phase Ib/II study are to determine the recommended dose of the anti-PD-1 mAb, MK-3475, in combination with standard dose trastuzumab, and to evaluate the efficacy and safety profile of the drug combination in patients with PD-L1 expressing, HER2-positive, unresectable loco-regional or metastatic breast cancer who have experienced progression during prior trastuzumabbased therapy.
Phase Ib part of the trial was completed in August 2015. |
|
| E.2.2 | Secondary objectives of the trial |
-Explore the efficacy & safety of the drug combination in pts with PDL1 negative, HER2-positive unresectable loco-regional or metastatic breast cancer who have experienced progression during prior trastuzumab-based therapy.
- Safety and tolerability
- Disease control (DC)
- Duration of response (DoR)
- Time to progression (TTP)
- Progression-free survival (PFS)
- Overall survival (OS)
Correlative objectives:
- Responses according to levels of PD-L1, of tumor infiltrating lymphocytes
- Responses according to ER Status, to FISH ratio and HER2 copy number
- Tumor dynamics during the disease course as well as emergence of new clones (ie resistance mechanisms)
- molecular characteristics profiles of responders & non-responders
Exploratory objectives:
- To describe TTP for patients with moderate partial response (MPR) compared with very good partial response (VGPR)
- To explore the prognostic ability of pre-treatment ER, PD-L1, and TILs with respect to MPR and VGPR |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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. |
|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib (dose finding): Dose-limiting toxicity of the anti-PD-1 mAb
MK-3475 in combination with standard dose trastuzumab
Phase II: Objective response (confirmed CR or PR as best overall
response) based on RECIST 1.1 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: Dose-limiting toxicity within the first cycle (21 days)
Phase II: Objective response determined by tumour assessment after 4 cycles (12 weeks), 6 cycles (18 weeks), 8 cycles (24 weeks) and then every 12 weeks (every 4 cycles) until confirmed progression |
|
| E.5.2 | Secondary end point(s) |
- Safety and tolerability as documented according to NCI-CTCAE
version 4.0
- Disease control (DC)
- Duration of response (DoR)
- Time to progression (TTP)
- Progression-free survival (PFS)
- Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DC: measured from the start of trial treatment until first documentation of progressive disease.
DoR: interval between dates of first documentation of objective response and first documentation of progressive disease.
TTP: interval between the dates of the start of trial treatment and first documentation of progressive disease.
PFS: time from start of trial treatment until documented disease progression or death, whichever occurs first.
OS: time from start of trial treatment to death from any cause.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Historic control: trastuzumab monotherapy after progression |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Patient accrual is expected to be completed within approximately 12-18 months after a start-up period of 6 months as the trial is activated by participating Centers. After cessation of treatment, patients will be followed in clinic until confirmed progression or 24 weeks after stop of treatment, whichever occurs first. Clinical visits will end approximately 3 years after enrollment of the first patient, and sites will be contacted for a final update on survival status of the patients. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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