BARBICAN: A randomised, open-label Phase II study to determine the contribution of ipatasertib to neoadjuvant chemotherapy plus atezolizumab in women with triple-negative breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Queen Mary University Of London

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516236-10-00

EudraCT number

2018-000977-62

ClinicalTrials.gov

NCT05498896

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Therapy, Efficacy

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.

Secondary objectives 6

1. Determine the response rates of the breast tumour and axillary nodes based on physical examination and imaging tests after treatment in both arms
2. Assess clinical response rate after taxanes plus atezolizumab in both groups.
3. To assess the effect of adding ipatasertib to atezolizumab on additional immune mediated biomarkers.
4. Determine the effect of ipatasertib on IEFS, DEFS and OS.
5. Evaluate PROs of health-related quality of life (HRQoL) associated with the addition of ipatasertib, as measured by the EORTC QLQ-C30
6. Assess the safety of each treatment arm.

Conditions and MedDRA coding

Triple-negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Willing and able to provide written informed consent prior to study entry
2. 2. Female ≥ 18 years of age
3. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
4. 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. 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. 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  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. 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. 8. Ability to comply with the protocol
9. 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

Exclusion criteria 32

1. 1. Evidence of metastatic breast cancer
2. 2. Received any systemic therapy (e.g. chemotherapy, targeted therapy, immune-therapy) or radiotherapy for current breast cancer disease before study entry
3. 3. Prior exposure to any CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, anti-PD-1 or anti-PD-L1 antibody
4. 4. Concurrent bilateral invasive breast cancer
5. 5. Inflammatory breast cancer
6. 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. 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. 8. Known intolerance to any of the study drugs (ie, paclitaxel, doxorubicin, epirubicin, cyclophosphamide) or any of their excipients
9. 9. Pre-existing peripheral neuropathy grade ≥ 2
10. 10. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with autoimmune-related hypothyroidism on a stable dose of thyroid replacement therapy may be eligible for the study following discussion with the medical monitor (See Appendix 1 for complete list)
11. 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. 12. History of idiopathic pulmonary fibrosis or organizing pneumonia
13. 13. History of HIV infection
14. 14. Known active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
15. 15. Active tuberculosis
16. 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. 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. 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. 19. Current treatment with anti-viral therapy for HBV
20. 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. 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. 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. 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. 24. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
25. 25. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry
26. 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. 27. Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy
28. 28. Pregnant or nursing women
29. 29. Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
30. 30. Clinically significant abnormalities of glucose metabolism as defined by any of the following: a. Glycosylated haemoglobin (HbA1C) ≥7.5% at screening (64 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) – 2.15] x 10.929) b. Fasting Plasma Glucose ≥ 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours c. 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
31. 31. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)
32. 32. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Clinical: • pCR is defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0) in all patients. • pCR is defined as no microscopic evidence of residual invasive tumour in all resected specimens of the breast and axilla (ypT0/is ypN0) in patients with or without PIK3CA/AKT1/PTEN genetic alterations.
2. Biological: 2-fold increase in GzmB+ CD8+ T cell levels from baseline to the end of each treatment phase.

Secondary endpoints 9

1. • Objective response rate (ORR) as assessed by RECIST 1.1 principles, defined as percentage of subjects with best overall response of complete response (CR) or partial response (PR) in the relevant analysis population.
2. • ORR.
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 (IFN 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. IEFS is further detailed according to the standardized STEEP system definition
5. • DEFS, 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Queen Mary University Of London

Sponsor organisation

Queen Mary University Of London

Address

327 Mile End Road

City

London

Postcode

E1 4NS

Country

United Kingdom

Scientific contact point

Organisation

Queen Mary University Of London

Contact name

Joint Research Medical Office

Public contact point

Organisation

Queen Mary University Of London

Contact name

Joint Research Medical Office

Locations

2 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications