Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Bevacizumab

Atezolizumab

Carboplatin

Antibodies

Antibodies, Monoclonal

Immunomodulating Agents

Immunoglobulins

Endothelial Growth Factors

Mitogens

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Immune Checkpoint Inhibitors

Atezolizumab 1200 mg Day 1 of each 21 day cycle IV, Bevacizumab 15 mg/kg Day 1 of each 21 day cycle IV, Gemcitabine 1000 mg/m2 Day 1 and 8 of each 21 day cycle IV, Carboplatin AUC 5 Day 1 of each 21 day cycle IV

Atezolizumab is a monoclonal antibody of IgG1 isotype PD-L1. It is used across a number of tumour types, both as a single-agent and in combination with other therapies such as chemotherapy.

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) which exerts its effect by inhibiting angiogenesis, a critical component of tumour growth and metastasis.

Gemcitabine is a type of chemotherapy drug

Carboplatin is platinum based chemotherapy drug

Stephen Luen, Dr

Prof Sherene Loi, Prof

Alexander Menzies

Kathryn Middleton

Amelia McCartney

Stephen Luen

The study hypothesise that the combination of carboplatin, gemcitabine, bevacizumab and atezolizumab may be synergistic and improve outcomes for patients with early relapsed TNBC by overcoming mechanisms of immune resistance and thus potentiating greater and more durable responses to immune checkpoint inhibitor therapy. Early relapsing TNBC represents a high priority, unmet need whereby effective therapeutic strategies are urgently needed.

This is a multi-center, single arm phase II study designed to evaluate the efficacy and safety of atezolizumab plus bevacizumab plus carboplatin plus gemcitabine in patients with locally recurrent, inoperable or metastatic recurrent PD-L1 positive or stromal TIL positive TNBC (Triple Negative Breast Cancer).

Assessment of Programmed death-ligand 1 (PD-L1) status will be available centrally for patients in which PD-L1 testing or stromal TIL testing has not been performed or is not available. In such cases, patients will be required to sign a pre-screening consent form allowing collection and testing of archival tumour samples for PD-L1 status. Patient's that are PD-L1 positive and who fulfil the remaining study eligibility criteria will then be offered participation into the main BELLA study.

Following confirmation of eligibility and registration to the main study, patients will receive treatment as outlined in Table 1 until disease progression according to RECIST 1.1, unacceptable toxicity or patient withdrawal. In the absence of disease progression, the discontinuation of atezolizumab, bevacizumab, carboplatin or gemcitabine (owing to AEs) can occur independently. In the event of ongoing clinical benefit but disease progression, treatment continuation may occur if approved by the CPI.

Table 1:

Order Treatment Dose Dose Frequency Route of Administration

1. Atezolizumab 1200 mg Day 1 of each 21 day cycle IV
2. Bevacizumab 15 mg/kg Day 1 of each 21 day cycle IV
3. Gemcitabine 1000 mg/m2 Day 1 and 8 of each 21 day cycle IV
4. Carboplatin AUC 5 Day 1 of each 21 day cycle IV

Tumour response will be evaluated according to RECIST 1.1. Any evaluable and measurable disease must be documented at screening and re-assessed every 6 weeks from cycle 1 - day 1, regardless of any dose delays.

CT or MRI scans should include chest, abdomen, and pelvis. CT or MRI scans of the brain should be completed at screening and subsequently performed if clinically indicated. At the Investigator's discretion, CT or MRI scans may be repeated at any time if progressive disease is suspected. Imaging based assessments should always be completed rather than clinical assessment to determine response.

Patients who discontinue treatment for any reason will have an End of Treatment visit 30 days after the last dose of treatment after which, patients will move into the follow-up phase of the study where they will be assessed on a 3 monthly basis. Patients with progressive disease will be followed for survival only and patients who discontinue treatment for other reasons will be followed for progression and survival. All patients will be followed up for 2 years after the last patient has been commenced treatment.

There will be 31 patients recruited into the study. If a patient does not receive any protocol treatments for any reason, that patient will be replaced in the study. There are no requirements for follow-up on patients who do not commence treatment.

It is expected that it will take 24 months to accrue the required 31 evaluable patients. Patients will be followed up until 2 years after the last patient has commenced treatment.

Translational Research:

1. Pre-treatment archival FFPE sample collected at pre-screening or screening for the main study will be tested retrospectively at the completion of the trial for

   Quantification of PD-L1 expression and Quantification of TILs on H\&E slides
2. Two fresh tumour tissue samples to be collected if deemed clinically feasible by the investigator: an "on-treatment" tumour sample should be collected during cycle 1, days 15-21 and a "post-progression" tumour sample should be collected ≥ 14 days after the last dose of bevacizumab, and prior to commence of a new therapy. On-treatment FFPE sample will be tested for

   Quantification of PD-L1 expression Quantification of TILs on H\&E slides
3. A whole blood sample will also be taken prior to the start of treatment, prior to day 1 of cycle 3, and at disease progression (EoT visit) for future research purposes for the assessment of biomarkers of immune activation in peripheral blood mononuclear cells.

Optional biomarker research:

1. If the patient has consented to the Optional Biomarker Study, an additional whole blood sample will be taken on Cycle 1 Day 1 prior starting the treatment for germline whole-genome SNP genotyping to be performed retrospectively.
2. If the patient has consented to the Optional Biomarker Study, stool samples for microbiome analysis will be collected prior to the start of treatment, prior to day 1 of cycle 3, and at disease progression (EoT visit). Microbiome analysis will be performed retrospectively.

This is a multi-center, single arm phase II study designed to evaluate the efficacy and safety of atezolizumab plus bevacizumab plus carboplatin plus gemcitabine in patients with locally recurrent, inoperable or metastatic recurrent PD-L1 positive or stromal TIL positive TNBC.

Evaluating the Efficacy and Safety of Bevacizumab, Carboplatin, Gemcitabine and Atezolizumab in Breast Cancer

A Single Arm Phase II Trial Evaluating the Efficacy and Safety of Bevacizumab, Carboplatin, Gemcitabine and Atezolizumab in Early Relapsing Metastatic Triple Negative Breast Cancer

Upon request, consideration by the Sponsor will be given to sharing reports and/or patient-level data with potential collaborators.

PFS is measured from treatment commencement to the first progression by RECIST 1.1, or death from any cause, whichever occurs first.

AEs using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

ORR, defined as the proportion of patients with an objective response (CR or PR) at any stage after commencement of treatment using RECIST 1.1 criteria

DOR is the time between the date of first response (CR/PR per RECIST1.1) to the date of first progression per RECIST1.1. Patients who died without progression will be censored on the date of their last tumour assessment.

OS is the time from treatment commencement to the date of death due to any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Evaluating the Efficacy and Safety of Bevacizumab, Carboplatin, Gemcitabine and Atezolizumab in Breast Cancer	NCT04739670	Metastatic Trip...	Atezolizumab Bevacizumab Gemcitabine Carboplatin	18 Years - 100 Years	Peter MacCallum Cancer Centre, Australia
Evaluating the Efficacy and Safety of Bevacizumab, Carboplatin, Gemcitabine and Atezolizumab in Breast Cancer	NCT04739670	Metastatic Trip...	Atezolizumab Bevacizumab Gemcitabine Carboplatin	18 Years - 100 Years	Peter MacCallum Cancer Centre, Australia

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