E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006188 |
E.1.2 | Term | Breast cancer female NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10006194 |
E.1.2 | Term | Breast cancer NOS stage I |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10006195 |
E.1.2 | Term | Breast cancer NOS stage II |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10006196 |
E.1.2 | Term | Breast cancer NOS stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine whether short-term pre-operative nivolumab either as monotherapy or in combination with ipilimumab or novel IO combinations can induce immune activation in early BC. |
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E.2.2 | Secondary objectives of the trial |
• To establish whether short-term pre-operative nivolumab either as monotherapy or in combination with ipilimumab or novel IO combinations is safe in early BC patients • To assess the proportion of clinical and radiological responses as measured by imaging • To assess the proportion of pathological responses (pCR, residual cancer burden) • To correlate parameters of systemic immune suppression in early BC with intratumoral immune landscape and with responses seen in patients • To correlate changes in tumor fragments (ex vivo model system, developed by Daniela Thommen) upon nivolumab either as monotherapy or in combination with ipilimumab or novel IO combinations with changes in the on-treatment biopsy • To explore the putative predictive value of upcoming biomarkers such as but not limited to: CD8, IFNy gene signature, mutational load, homologous recombination deficiency (HRD) • To evaluate 3-year, 5-year and 10-year overall and event free survival rate
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Signed written informed consent • 18 years or older at moment of inclusion; • Female and male gender; • WHO performance status 0 or 1; • Resectable primary breast cancer stage I-III. Nodal status must be examined by ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan (cohort 3B, 4B and 5B: PET-CT mandatory). • Patients indicated for neoadjuvant chemotherapy will also be eligible, whereby a new dedicated biopsy is performed before the beginning of the chemotherapy. Adjuvant systemic treatment is allowed if indicated according to local guidelines. • The tumors must be: o at least 5 mm (minimum cT1b) as determined by MRI o TNBC defined as ER<10%, HER2-negative OR luminal B defined as ER≥10%, HER2-negative with either Ki67≥20% or PR ≤20% OR grade 3. HER2 negative is defined as an IHC score of <2 or 2+ with a negative ISH. o For TNBC patients: TIL≥5% o For LumB breast cancer patients: TIL≥1% o For cohort 3B: N0 status o For cohort 4B: N0 status, TNBC and TIL 30-49% o or cohort 5B: N0 status, TNBC and TIL ≥50%
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E.4 | Principal exclusion criteria |
• evidence or suspicion of metastatic disease. Evaluation of the presence of distant metastases may include chest X-ray, liver ultrasound, isotope bone-scan, CT-scan of chest and abdomen and/or FDG-PET scan, according to local procedures; • other prior invasive malignancy 1) in the breast or 2) localized in the near proximity of the breast, that was treated with radiotherapy at the localization of the new breast tumor; • Concurrent ipsilateral or contralateral disease of the primary or a secondary tumor is allowed, as long as the other lesions is not a distant metastasis. • Locoregional recurrences are not allowed. Second primary tumors are allowed in the study; • occult breast cancer; • previous anti-cancer hormone therapy or chemotherapy; • prior treatment with checkpoint inhibitors (including anti- PD1, -PD-L1, -CTLA-4, -LAG3); • concurrent anti-cancer treatment, neoadjuvant therapy or another investigational drug; |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pathological complete response rate per cohort, with a pCR defined as no residual invasively growing tumor cells detected by microscopic examination in breast and axilla (the presence of carcinoma in situ will be recorded separately; when only carcinoma in situ is present, patients will be recorded as having a pCR.)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
from baseline up to one year after surgery |
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E.5.2 | Secondary end point(s) |
• Safety will be monitored by incidence, nature and severity of Adverse Events graded according to NCI-CTCAE v5.0 collected during treatment and up to 3 weeks post-surgery. In addition, we hypothesize that the pre-operative immunotherapy does not result in significant delay or cancelation of breast surgery or (neo)adjuvant systemic treatment in at least 95% of patients • Radiological response using breast MRI per cohort; • Event-free survival (EFS), defined as the interval from registration to the earliest occurrence of disease progression resulting in inoperability, invasive loco regional recurrence, distant metastasis, or death from any cause, whichever comes first. • Overall survival (OS), defined as the time from registration to death from any cause.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 10 years after surgery |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | No |
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 | No |
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 | 1 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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 | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |