| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Inflammatory breast cancer |
| Cancer du sein inflammatoire |
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| E.1.1.1 | Medical condition in easily understood language |
Inflammatory breast cancer
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| Cancer du sein inflammatoire |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021974 |
| E.1.2 | Term | Inflammatory breast cancer |
| E.1.2 | System Organ Class | 100000020817 |
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| 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 |
- To assess pathological complete response rate (ypT0/Tis, ypN0) following neoadjuvant FEC/EC-paclitaxel chemotherapy plus pembrolizumab,
- To assess separately in a run-in phase if neoadjuvant chemotherapy with anthracycline-based induction (FEC if HR-positive IBC or dose-dense EC if HR-negative IBC) + Q3W pembrolizumab exposes IBC patients to significant toxicity rates.
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| E.2.2 | Secondary objectives of the trial |
-To describe the safety profile and tolerability of pembrolizumab in combination with neoad-juvant (F)EC-paclitaxel chemotherapy.
-To estimate in each arm the pathological complete response rates, invasive disease-free, event-free and overall survivals
-To obtain pre- and post- treatment tissue and blood samples for pharmacodynamic measurements and biological /immunological correlates.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 years or older,
2.Performance status 0 to 2,
3.Able to comply with the protocol,
4.Patient affiliated to the national “Social Security” regimen or beneficiary of this regimen,
5.Patient must have signed a written informed consent form prior to any study specific screening procedures,
6.Previously untreated, histologically confirmed breast cancer and confirmed inflammatory breast cancer defined as follows:
- T4d any N following American Joint Committee on Cancer (AJCC)-7th version classification: diffuse Erythema and edema ("peaud'orange") of the breast, occupying at least 1/3 of the breast, with or without underlying palpable mass
7. HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluores-cent/chromogenic in situ hybridization (FISH- or CISH-)
8. Hormone receptors status known,
9. No metastases,
10.Adequatehematologic function: absolute neutrophil count ≥ 1.2 x 109/L AND platelets ≥ 100 x 109 AND Hb ≥ 9 g/dL,
11.Adequate liver function: total bilirubin ≤ 1.5 ULN unless elevation is due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin AND - ASAT < 2.5 ULN AND ALAT < 2.5 ULN,
12.Adequate kidney function: serum creatinine ≤ 1.25 ULN or creatinine clearance ≥ 50 mL/min according to the Cockroft and Gault formula AND no proteinuria (> 1 g/24 hours),
13.Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ultrasound methods),
14.International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 ULN AND normal TCA unless subject is receiving anticoagulant therapy, as long as PT or TCA is within therapeutic range of intended use of the anticoagulants,
15. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of child bearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject,
16. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required,
17. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. |
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| E.4 | Principal exclusion criteria |
1. Has metastatic breast cancer,
2. Has HER2-positive breast cancer,
3. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment,
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment,
5. Has a known history of active TB (Bacillus Tuberculosis)
6.Hypersensitivity to pembrolizumab or any of its excipients,
7. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy,
8. Has a known additional malignancy that progressed or required treatment in the last 5 years, Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer,
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment,
10. Has history of/active pneumonitis requiring treatment with steroids or has history of/active interstitial lung disease,
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator,
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial,
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment,
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent,
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),
17. Has known active Hepatitis B (e.g., HBs Ag reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected),
18. Has received a live vaccine within 30 days of planned start of study therapy. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Central evaluation of pathological complete response rate as defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system)
- Dose Limiting Toxicity (DLT) rates as defined as incidence of DLT during the 21 days following the first administration of pembrolizumab in combination with FEC/EC, will be assessed separately in the first 6 patients of each stratum (HR+ and HR-).
DLTs will be defined according to CTCAE as:
o any drug-related > or equal to grade 3 extra-hematologic; exception will be made for non-clinically significant clinical or laboratory toxicities such as :
- Nausea, vomiting, diarrhea without maximal symptomatic/prophylactic treatment and/or hypophosphatemia without maximal treatment
- Grade 3 skin rash that can be controlled with standard therapy
- Transient, less than 7 days, Grade 3 elevations of ALT and/or AST without evidence of other hepatic injury in the blood tests,
- Grade 3 hyperglycemia, hypertriglyceridemia or hyperlipidemia that can be controlled with standard therapy
- Grade 3 or 4 asymptomatic amylase or lipase elevation
- Grade 3 asymptomatic CPK elevation
- Any grade 3 or 4 asymptomatic biological toxicity considered as nonclinically relevant after discussion with the principal investigator, e.g. GGT elevation
o Any ≥Grade 3 thrombocytopenia with clinically significant bleeding
o CTCAE Grade 4 hematological toxicity of >7 days duration excluding lymphopenia
o Febrile grade 4 neutropenia requiring hospitalization.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
pCR: at surgery
DLT: 21 days following the first administration of Pembrolizumab |
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| E.5.2 | Secondary end point(s) |
1- occurrence of serious adverse events and adverse events starting grade 2 or grade 1 (run-in period) according to the National Cancer Institute (NCI) Common Terminology Criteria for Ad-verse Events (CTCAE) V4.03
2- Local evaluation of pathological complete response rate as defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system)
2- Invasive disease-free survival (IDFS), as defined as time from surgery to the first docu-mented occurrence of an event, defined as:
- Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast as the original primary lesion),
- Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast),
- Distant recurrence (i.e., evidence of breast cancer, excluding ipsilateral invasive or local-regional breast cancer, in any anatomic site that has been either histologically confirmed or clinically diagnosed as recurrent invasive breast cancer),
- Contralateral invasive breast cancer,
- Death from any cause,
3- Event free survival (EFS), defined as time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive or non-invasive]), or death from any cause),
4- Overall survival (OS), defined as time from randomization to death from any cause
5- Other endpoints (ancillary studies):
- Evaluation of PD-L1 expression in pre, per and post-treatment tissue by IHC and mass spectrometry-based proteomics; PD-L1 will be also evaluated in plasma samples using quantitative proteomics,
- Immunomonitoring on blood and tissue samples,
- Next generation sequencing, CGH arrays and mRNA expression on baseline tumor tissue,
- Measurement of baseline CTC for prospective validation of their prognostic value in IBC,
- Purification of ctDNA for disease monitoring and specific sequencing will also be carried out-Specific approaches to be developed on post-treatment residual disease (immune profiling, NGS and mouse xenografing for ex-vivo phenotypic approaches ) in order to identify mechanisms of resistance.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- local elevation of pCR: surgery
2- IDFS: surgery, first occurence of any of listed event
3- EFS: randomization, date of progression, recurrence
4: OS: randomization, date of death of any cause
5- endpoints ancillary study: inclusion, before paclitaxel, before surgery, before radiotherapy, at progression. |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| 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 | Yes |
| 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 |
| Standard neoadjuvant chemotherapy |
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| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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