| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple negative breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer negative for oestrogen receptor, progesterone receptor and HER2 |
|
| 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 | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
BARBICAN has a joint clinical and biological primary objective:
Clinical: To compare the pathologic complete response (pCR) rates of NACT plus atezolizumab with NACT plus atezolizumab plus Ipatasertib in patients with or without PIK3CA/AKT1/PTEN genetic alterations.
Biological: To determine whether adding the AKT-inhibitor ipatasertib to atezolizumab and chemotherapy increases the probability of an immune response over adding atezolizumab to chemotherapy in all treated patients. |
|
| E.2.2 | Secondary objectives of the trial |
- Determine the response rates of the breast tumour and axillary nodes based on physical examination and imaging tests after treatment in both arms.
- Assess clinical response rate after taxanes plus atezolizumab in both groups
- To assess the effect of adding ipatasertib to atezolizumab on immune mediated markers.
- Determine the effect of ipatasertib on IEFS, DEFS and OS
- Evaluate PROs of health-related quality of life (HRQoL) associated with the addition of ipatasertib, as measured by the EORTC QLQ-C30
- Assess the safety of each treatment arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent prior to study entry
2. Female ≥ 18 years of age
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
4. Histologically confirmed TNBC defined as:
•ER negative with <1% of tumour cells positive on IHC or an IHC score (Allred) of ≤2
• PR unknown or negative with <1% of tumour cells positive on IHC or Allred score of ≤2
• HER2 negative with 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH
5. Node-positive (cT1-4 cN1-2 M0) and/or tumour size ≥2 cm (cT2-T4 cN0-2 M0) with no prior treatment; participants
entering the trial after undergoing a SLN biopsy will be eligible if they meet other entry criteria
6. Adequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the
following:
a. ANC ≥ 1500 cells/μL (1.5 x 109/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to
Cycle 1, Day 1)
b. Platelet count ≥ 100,000/μL (100 x 109/L) (without transfusion within 2 weeks prior to Cycle 1, Day 1)
c. Haemoglobin ≥ 9.0 g/dL (90g/L) (patients may be transfused or receive erythropoietic treatment to meet this
criterion).
d. INR or aPTT ≤ 1.5 x ULN (for patients not receiving therapeutic anticoagulation. Patients receiving therapeutic
anticoagulation must be on a stable anticoagulant regimen.
e. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance 50 ml/min
f. AST or ALT and ALP < 2.5 times the institutional upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN (patients with
known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled).
7. Patients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test within 14
days of Day 1 Cycle 1 of study treatment, preferably as close to the first dose as possible. Patients must agree to use
adequate contraception, defined as those methods with a failure rate of < 1 % per year, (see section 6.14) beginning
14 days before the first dose of study drug and for 12 months after the last dose of cyclophosphamide (or 5 months
after the last dose of atezolizumab, whichever is longer).
8. Ability to comply with the protocol
9. Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples (at least 2 core needle biopsies)
with an associated pathology report, determined to be available and sufficient for central testing OR tumour accessible
for biopsy. |
|
| E.4 | Principal exclusion criteria |
1. Evidence of metastatic breast cancer.
2. Received any systemic therapy or radiotherapy for current breast cancer disease before study entry
3. Prior exposure to any CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, anti-PD-1 or anti-PD-L1 antibody.
4. Concurrent bilateral invasive breast cancer
5. Inflammatory breast cancer
6. Active malignancy (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) within the past 36 months prior to study entry
7. Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment; minor surgeries including insertion of an indwelling catheter, core needle biopsy, or sentinel lymph node biopsy is allowed.
8. Known intolerance to any of the study drugs or any of their excipients
9. Pre-existing peripheral neuropathy grade ≥ 2
10. History of autoimmune disease
11. History of Type I or Type II diabetes mellitus requiring insulin. Patients who are on a stable dose of oral diabetes medication ≥ 2 weeks prior to initiation of study treatment are eligible for enrolment.
12. History of idiopathic pulmonary fibrosis or organizing pneumonia
13. History of HIV infection
14. Known active hepatitis infection or hepatitis C.
15. Active tuberculosis
16. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
17. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
18. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
19. Current treatment with anti-viral therapy for HBV
20. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
21. Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) use for ≥28 days at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids
for at least two weeks before randomisation are allowed.
22. Significant cardiovascular disease, such as:
• History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months.
• Congestive heart failure (CHF) New York Heart Association (NYHA) Class III or IV or history of CHF NYHA class III or IV, unless an echocardiogram or multigated acquisition scan performed within 3 months before day 1 reveals a left ventricular ejection fraction ≥ 50%;
23. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
24. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
25. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry.
26. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
27. Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy
28. Pregnant or nursing women
For Atezolizumab + Ipatasertib arm only
1. Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications.
2. Clinically significant abnormalities of glucose metabolism
3. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
4. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical: pCR defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0) in all patients and in patients with or without PIK3CA/AKT1/PTEN genetic alterations
Biological: 2-fold increase in GzmB+ CD8+ T cell levels from baseline to the end of each treatment phase |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the time of definitive surgery following completion of study treatment. |
|
| E.5.2 | Secondary end point(s) |
1. Objective response rate (ORR) as assessed by RECIST 1.1 principles, defined as percentage of subjects with at least one instance of complete response (CR) or partial response (PR) in the relevant analysis population
2. ORR based on clinical assessment
3. Status and changes of the biomarkers listed below in pre- and end-of treatment tumour and/or blood samples:
immune phenotyping, CD8, PD-L1 & MHC-I, immune infiltrates (IFNgamma gene signature expression).
4. IEFS, defined as the time from randomisation to date of first treatment failure that is invasive loco‐regional or distant recurrence or new invasive cancer or death from any cause.
5. DDFS, defined as the time from randomisation to the date of first distant recurrence or death attributable to any cause, including breast cancer, non‐breast cancer, or unknown cause. Distant recurrence is defined as metastatic disease‐breast cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer.
6. OS, defined as time from randomisation to death of any cause
7. Assessment of mean changes in function and disease/treatment-related symptoms in all scales of the EORTC QLQ-C30 by treatment arm
8. Health utility assessment as measured by the EQ-5D during the study for health economic evaluations
9. Incidence, nature and severity of adverse events with severity determined according to CTCAE v4.03. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. As indicated per local guidelines- after completion of neoadjuvant treatment and prior to surgery (min 3 weeks after last dose, max 1 day prior to surgery), or sooner if clinically indicated. Thereafter, annual mammogram (or MRI of the breast) for 5 years, unless patient had bilateral mastectomy.
2. As per endpoint 1
3. Pre-, during and post-treatment samples
4. Same as endpoint 1
5. Same as endpoint 1
6. Death at any timepoint
7 & 8. Baseline, C3, 5, 7, pre-surgery, every 4mos Yr 1&2 and 6monthly Yr 3 to 5
9. From consent to 135 days after last dose of atezolizumab |
|
| 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 | 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) | 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 | 39 |
| 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
|
| The end of study is defined as last patient last data collection, which for the primary and secondary analysis is expected to occur approximately by the LPLV time point allow for the centralisation of tumour samples and biomarker analysis. All exploratory research will be completed by LPLV. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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