Investigate the Contribution of Ipatasertib to Neoadjuvant Chemotherapy Plus Atezolizumab in TNBC

Study Overview
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Brief Summary
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International, randomised, open label, neo-adjuvant phase II trial in women with newly diagnosed, non-metastatic, high-risk (node positive and/or tumour size ≥ 2cm), triple negative breast cancer. The study aims to evaluate the effects of adding ipatasertib to chemotherapy and atezolizumab in patients with and without PI3CA/AKT1/PTEN genetic alterations.

Official Title
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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

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Ipatasertib
* Drug: Paclitaxel
* Drug: Doxorubicin
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent prior to study entry Female ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 Histologically confirmed TNBC Node-positive (cT1-4 cN1-2 M0) and/or tumour size ≥2 cm (cT2-T4 cN0-2 M0) with no prior treatment Adequate haematologic and end-organ function . Patients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test. Patients must agree to use adequate contraception Ability to comply with the protocol Representative formalin-fixed paraffin embedded breast tumour samples with an associated pathology report, determined to be available and sufficient for central testing OR tumour accessible for biopsy Exclusion Criteria: Evidence of metastatic breast cancer. Any systemic therapy (e.g. chemotherapy, targeted therapy, immune-therapy) or radiotherapy for current breast cancer disease before study entry Prior exposure to any CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, anti-PD-1 or anti-PD-L1 antibody Concurrent bilateral invasive breast cancer Inflammatory breast cancer 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 Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment Known intolerance to any of the study drugs (ie, paclitaxel, doxorubicin, epirubicin, cyclophosphamide) or any of their excipients Pre-existing peripheral neuropathy grade ≥ 2 History of autoimmune disease 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 History of idiopathic pulmonary fibrosis or organising pneumonia History of HIV infection Known active hepatitis infection or hepatitis C. Active tuberculosis 19. Current treatment with anti-viral therapy for HBV 20. Treatment with systemic immunostimulatory agents 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. 22. Significant cardiovascular disease 16. Severe infection within 4 weeks prior to initiation of study treatment 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 29. Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications 30. Clinically significant abnormalities of glucose metabolism 31. History of or active inflammatory bowel disease or active bowel inflammation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Atezolizumab + Chemotherapy<br>Atezolizumab (1200mg IV Q3W x 1 cycle) followed by Paclitaxel (80 mg/m2 Q1W x 12) plus Atezolizumab 840 mg (Q2W x 6) followed by Doxorubicin (60 mg/m2) plus Cyclophosphamide (600 mg/m2 Q2W x 4) plus Atezolizumab (840 mg Q2W x 4) | Drug: Atezolizumab<br>* IV infusion<br>* Other names: Tecentriq;Drug: Paclitaxel<br>* IV infusion<br>Drug: Doxorubicin<br>* IV infusion<br>Drug: Cyclophosphamide<br>* IV infusion<br>|
| Experimental: Atezolizumab + Chemotherapy + Ipatasertib<br>Atezolizumab (1200 mg, Q3W x 1 cycle), plus Ipatasertib (400 mg OD, days 1-14) followed by Paclitaxel (80 mg/m2 Q1W x 12) plus Atezolizumab (840 mg Q2W x 6), plus Ipatasertib, (400 mg OD, days 1-21 Q4W) followed by Doxorubicin (60 mg/m2) plus Cyclophosphamide (600 mg/m2 Q2W x 4) plus Atezolizumab (840 mg Q2W x 4). | Drug: Atezolizumab<br>* IV infusion<br>* Other names: Tecentriq;Drug: Ipatasertib<br>* Oral<br>Drug: Paclitaxel<br>* IV infusion<br>Drug: Doxorubicin<br>* IV infusion<br>Drug: Cyclophosphamide<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR | pCR defined as no microscopic evidence of residual invasive tumour | Time of definitive surgery (6 months after start of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | 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. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PI3CA/AKT1/PTEN genetic alterations, Newly diagnosed TNBC, Ipatasertib, Atezolizumab, Neo-adjuvant