| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) |
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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 | PT |
| E.1.2 | Classification code | 10006198 |
| E.1.2 | Term | Breast cancer recurrent |
| 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 | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| 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 | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| 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 |
PHASE I: To confirm the safety of oleclumab in combination with paclitaxel, carboplatin and durvalumab in previously untreated, locally recurrent inoperable or metastatic TNBC patients.
PHASE II: To evaluate the clinical benefit of oleclumab in combination with paclitaxel, carboplatin and durvalumab in previously untreated, locally recurrent inoperable or metastatic TNBC patients by the comparing the clinical benefit rate (CBR) at 24 weeks from the 1st dose of study drug administration between patients treated with or without the anti-CD73 antibody oleclumab.
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| E.2.2 | Secondary objectives of the trial |
PHASE I: To determine the recommended phase II dose (RP2D) of oleclumab in combination with paclitaxel, carboplatin and durvalumab in previously untreated, locally recurrent inoperable or metastatic TNBC patients.
PHASE II:
1) To evaluate the efficacy of oleclumab assessed by comparing the objective response rate (ORR; complete response [CR] + partial response [PR]) and the duration of response (DOR) between patients treated with or without the anti-CD73 antibody oleclumab.
2) To evaluate the survival benefit in previously untreated locally recurrent inoperable or metastatic TNBC patients by comparing the progression-free survival (PFS) and overall survival (OS) between patients treated with or without the anti-CD73 antibody oleclumab.
3) To evaluate the safety and feasibility of oleclumab in combination with paclitaxel, carboplatin and durvalumab
4) To evaluate the efficacy, clinical and survival benefits according to PD-L1 and CD73 expression.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age of ≥ 18 years
2. Female
3. Life expectancy of a least 12 weeks
4. Body weight above 35kg
5. The locally recurrent or metastatic relapse must be histologically confirmed TNBC in patients not previously treated with systemic treatment and which cannot be treated with curative intent. Newly diagnosed patients with de-novo metastatic disease are eligible
6. Estrogen receptor (ER) and progesterone receptor (PR) negativity (< 1% positive staining cells in the invasive tumour) determined locally using IHC per ASCO/CAP criteria)62
7. Human epidermal growth factor receptor 2 (HER2) negativity (negative IHC staining [score 0 or 1] or negative fluorescence in situ hybridization [FISH] based on the ASCO/CAP guidelines and recommendations) and determined locally63
Note: patients initially diagnosed with hormone receptor–positive and/or HER2-positive breast cancer OR de novo metastatic patients with a primary tumour hormone receptor-positive (weak positivity or ER negativity and PR positivity) considered as non-clinically relevant are eligible if the tumour biopsy obtained from a local recurrence or distant metastasis site confirms the TNBC disease.
8. Confirmed tumour PD-L1 and CD73 IHC assessment as documented through central testing of a representative tumour tissue specimen for stratification purposes (only for phase II).
9. Provision of recurrence/metastatic tissue samples from resections, core-needle biopsies or excisional, incisional, punch, or forceps biopsies:
- At least 1 FFPE [Formalin-Fixed paraffin-embedded] tumour tissue and 1 frozen core as a priority, if feasible 2 additional fresh tumour tissue cores should be collected too.
- Fine-needle aspiration (FNA) (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), brushing, and cell pellets from cytology samples are not acceptable.
Note 1: If the subject has just performed a metastatic lesion biopsy, she is eligible only if a FFPE tissue sample (or at least 20 unstained slides, freshly cut for the purposes of the study) of the metastatic/recurrent lesion is available. In this situation only, frozen cores are not mandatory.
Note 2: In case of a de-novo metastatic disease, if the biopsy of a metastatic lesion is not feasible, the patient is eligible if primary tumour lesion samples (FFPE + frozen cores) are available.
10. Provision of an archived FFPE diagnostic biopsy or surgical primary breast tumour sample (or at least 20 unstained slides, freshly cut for the purposes of the study).
Note: In case of neoadjuvant treatment (before surgery), the diagnostic biopsy is preferable.
11. At least 6 months elapsed between the completion of surgical and/or systemic treatment with curative intent (e.g., the date of primary breast tumour surgery or the date of last adjuvant chemotherapy administration (radiotherapy is not included), whichever occurred last) and first documented local or distant disease recurrence (NOTE: not applicable for de-novo metastatic disease)
12. At least one measurable disease based on RECIST v1.1. Tumour lesions in a previously irradiated area are considered measurable, if progression has been demonstrated in such lesions
13. Adequate organ function:
a) Absolute neutrophil count (ANC) ≥ 1500/μl (without the addition of growth factors)
b) Platelets [PLT] ≥ 100000/μl (without the addition of growth factors/prior transfusions)
c) Hemoglobin (Hb) ≥ 10 g/dl (without the addition of growth factors/prior transfusions)
d) Creatinine ≤ 1.5 x upper limit of normal (ULN) OR estimated glomerular filtration rate (eGFR) ≥ 60 ml/min as calculated using the method standard for the institution. If eGFR is lower than 60 ml/min, a 24-hour urine creatinine clearance can be performed to rule out an underestimation of the eGFR.
e) Total serum bilirubin (TBL) ≤ 1.5 x ULN unless the subject has documented Gilbert syndrome in which case up to 3 x ULN is acceptable
f) Aspartate and alanine aminotransferase (AST/ALT) ≤ 2.5 x ULN unless liver metastases are present, in which case it must be ≤ 5 x ULN
g) International Normalized Ratio (INR) ≤ 1.5 x ULN unless subject is receiving
anticoagulant therapy as long as INR and activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
14. Performance status (PS) of 0 or 1 on the ECOG Performance scale
15. Female subjects of childbearing potential (FSCP) must be willing to use one highly effective method of contraception (detailed at protocol section 6.6.) for the course of the study through 6 months after the last study drug administration. FSCP must have a negative serum pregnancy test done within the 28 days before treatment start. FSCP are those who have not been surgically sterilized or have not been free of menses for at least 1 year.
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| E.4 | Principal exclusion criteria |
1. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
a) Patients with vitiligo or alopecia
b) Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
c) Any chronic skin condition that does not require systemic therapy
d) Patients without active disease in the last 5 years may be included but only after consultation with the sponsor
e) Patients with celiac disease controlled by diet alone
2. Current or prior treatment with immunosuppressive medication within 14 days prior to enrolment. The following are exceptions to this criterion:
a) Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
c) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
3. Any live, attenuated vaccine administered within 28 days prior to enrolment or anticipation that such a live attenuated vaccine will be required during the study
4. Chronic daily treatment with non-steroidal anti-inflammatory drug (NSAID) (occasional use for the symptomatic relief of medical conditions, for example, headache, fever is allowed)
5. Active infection including
a) Tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
b) Hepatitis B (known positive HBV surface antigen (HBsAg) result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody
c) Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
d) Human immunodeficiency virus (positive HIV 1/2 antibodies).
6. Treatment with systemic immunostimulatory agents, including but not limited to, interferon (IFN)-alpha, IFN-beta, interleukin (IL)-2, conjugated IL-2 cytokines within 42 days or five half-lives of the drug, whichever is longer, prior to screening
7. Previous treatment with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1 including durvalumab, anti-Cytotoxic T-lymphocyte-associated molecule-4), anti-CD73 antibodies, adenosine A2A receptor antagonists, or prior treatment with CD137
agonists/OX-40 agonists or any other antibody or drug targeting T-cell co-stimulation or other immunomodulatory therapies
8. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo and the laboratory values defined in the inclusion criteria
9. Known hypersensitivity reactions to the study drugs or to any of the excipients, pre-medications (acetaminophen/paracetamol, diphenhydramine or equivalent anti-histamine and methylprednisolone or equivalent glucocorticoid) and to other platinum containing compounds
10. Untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases with local treatment (stereotactic radiosurgery or whole brain radiation therapy) may participate provided they have stable brain metastases on a recent brain MRI (performed during the 2 weeks prior inclusion) and have measurable disease outside the CNS.
Note: Known brain metastases are considered active (and not eligible for trial), if any of the following criteria are applicable: a) Recent brain imaging demonstrates progression of existing and/or appearance of new lesions
b) Neurological symptoms attributed to brain metastases have not returned to baseline
c) Steroids were used for management of symptoms related to brain metastases within 14 days of enrolment
d) Completion of local therapy for brain metastases within 28 days of enrolment
11. Major surgical procedure (as defined by the principal investigator) within 28 days prior to enrolment. Note: Local surgery of isolated lesions for palliative intent is acceptable.
12. Uncontrolled intercurrent illness, including but not limited to,
a) Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia. Patients previously treated with anthracyclines are eligible if a recent cardiac work up (< 6 months) demonstrated a normal left ventricular ejection fraction (LVEF≥50%).
b) Interstitial lung disease
c) Serious chronic gastrointestinal conditions associated with diarrhoea
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PHASE I: Safety and tolerability will be assessed by monitoring frequency, duration and severity of adverse events (AEs).
PHASE II: Clinical benefit (CB). CB is defined as a patient who achieved CR or PR or demonstrated SD at 24 weeks from the 1st dose of study drug administration based on RECIST v1.1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
PHASE I: Safety and tolerability will be assessed by monitoring frequency, duration and severity of adverse events (AEs) including Dose limiting toxicities (DLTs) as defined per protocol.
PHASE II:
1) Objective Response. OR is defined as a patient (in the intent-to treat population) who achieved a CR or PR as best overall response (BOR) based on RECIST v1.1.
2) Duration of Response. DOR is defined as the time from documentation of first tumour response to disease progression based on RECIST v1.1.
3) Progression Free Survival. PFS is defined as the time from 1st study drug administration to the first documented disease progression based on RECIST v1.1 or death due to any cause, whichever occurs first. (Subjects who are alive and progression free at the time of analysis will be censored at the time-point of their last tumour assessment by imaging.)
4) Overall Survival. OS is defined as the time from 1st study drug administration to death due to any cause. (Subject without documented death at the time of the analysis will be censored at the date of the last follow-up.)
5) Frequency, duration and severity of AEs assessment based on CTCAE 5.0.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | 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 |
| to define the recommended phase II dose (RP2D) of oleclumab |
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| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase I : 1 arm to define the recommended phase II dose (RP2D), Phase II : randomized, open-label |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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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The end of study is declared when all the following criteria have been met:
• Approximately 24 months after the date the last patient has been randomized.
• Until every patient reached PD or died or withdrew consent or is lost to follow-up
• The database has been fully cleaned and frozen for all analyses
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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