E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Triple negative breast cancer (TNBC) patients with metastatic disease |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancer, triple negative, metastastic |
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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 | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000020826 |
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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 the activity of nivolumab after four different immune response induction treatments in TNBC patients with metastatic disease. We hypothesize that short-term induction treatment induces an anticancer immune response resulting in increased activity of nivolumab as compared to unprimed, single agent nivolumab. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of nivolumab treatment after short-term induction therapy with radiation, doxorubicin, cyclophosphamide or cisplatin. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Metastatic triple negative breast cancer with conformation of ER and HER2 negativity (ER <10%, and HER2 0,1 or 2 in the absence of amplification as determined by in situ hybridization) on a histological biopsy of a metastatic lesion
• 18 years or older
• Metastatic lesion accessible for histological biopsy (Mandatory biopsies: pre-treatment induction treatment, post-induction treatment, 12-weeks. Optional biopsies: at progression, of irradiated site)
• Maximum of three previous lines of chemotherapy for metastatic disease
• Evaluable disease according to RECIST 1.1
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E.4 | Principal exclusion criteria |
• known history of leptomeningeal disease localization
• history of having received other anticancer therapies within 2 weeks of start of the study drug
• history of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mgl daily prednisone equivalents) or chronic infections.
• prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody
• live vaccine within 30 days of planned start of study therapy.
• active other cancer
• positive test for hepatitis B surface virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• current pregnancy or breastfeeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Progression-free survival (PFS, time from randomisation to tumor progression or death) Progression as defined by RECIST 1.1 will be used.
• For the first stage of the trial, proportion of patients with PFS of at least 12 weeks in each treatment arm. Treatment arms with >30% of patients with PFS of at least 12 weeks will continue to stage II of the study. Progression as defined by RECIST 1.1 will be used.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
week 6, week 12 and every 12 weeks thereafter until progression of disease |
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E.5.2 | Secondary end point(s) |
• Progression-free survival (=PFS1, time from randomization to tumor progression or death from any cause) Progression as defined by modified RECIST 1.1 for immune-based therapeutics (iRECIST) ]will be used.
• Progression-free survival (=PFS2, time from nivolumab treatment initiation to tumor progression) Progression as defined by RECIST 1.1 and iRECIST will be used.
• Overall response rate ORR (complete response CR or partial response PR) according to RECIST 1.1 and iRECIST will be used.
• Clinical benefit rate (CR+PR+stable disease ≥ 6 months and CR+PR+stable disease ≥ 3 months) according to RECIST 1.1 [10] and iRECIST will be used.
• Overall survival (OS, time from start nivolumab to death from any cause)
• Percentage of patients with toxicity (classified according to CTCAE v4.0 and immune-related toxicity
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Response; week 6, week 12 and every 12 weeks thereafter until progression of disease
Toxicity; every 2 weeks until 30 days after last treatment |
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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 | 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 | 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 | 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 |
Different types of immune response induction treatments |
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E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 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 | 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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |