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

NCT04739670 | Recruiting Phase 2 DMC

• 1 other identifier: 19/002
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Metastatic Triple Negative Breast Cancer

Keywords

Triple Negative Breast Cancer; TNBC; Early relapse; immunotherapy; PD-L1; stromal TILs

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

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

  Assessed after commencement of treatment, until the last registered patient has been followed up for 2 years.

Secondary Outcomes (4)

• Adverse events (AEs)

  Through completion of treatment, maximum 30 months

• Objective Response Rate(ORR)

  Through Study completion, until the last registered patient has been followed up for 2 years.

• Duration of response (DOR)

  Through Study completion, until the last registered patient has been followed up for 2 years.

• Overall survival (OS)

  Through Study completion, until the last registered patient has been followed up for 2 years.

Study Arms (1)

Atezolizumab, Bevacizumab, Gemcitabine and Carboplatin

EXPERIMENTAL

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

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Gemcitabine; Drug: Carboplatin

Interventions

Atezolizumab DRUG

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.

Atezolizumab, Bevacizumab, Gemcitabine and Carboplatin

Bevacizumab DRUG

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.

Atezolizumab, Bevacizumab, Gemcitabine and Carboplatin

Gemcitabine DRUG

Gemcitabine is a type of chemotherapy drug

Atezolizumab, Bevacizumab, Gemcitabine and Carboplatin

Carboplatin DRUG

Carboplatin is platinum based chemotherapy drug

Atezolizumab, Bevacizumab, Gemcitabine and Carboplatin

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have provided written informed consent
• Male or female aged 18 years or over
• Histologically documented triple negative breast cancer (TNBC) that is locally advanced or metastatic and is not amenable to resection with curative intent Receptor status at study entry should correspond to the evaluation of the most recent biopsy as assessed locally TNBC for this study is defined as human epidermal growth factor receptor 2 (HER2)-negative by ASCO-CAP 2018 guidelines, and estrogen receptor (ER) expression \< 10%, and progesterone receptor (PgR) expression \< 10%
• PD-L1 positive tumour or tumour-infiltrating lymphocyte-positive defined as:
• Immune cell PD-L1 expression ≥ 1% via SP142 assay via local or central lab OR Stromal TILs ≥ 5% by assessment on H\&E stained tumour sections via local laboratory Note: Where possible, local or central testing should be done on the most recently available tumour specimen and must have been obtained within 12 months prior to the date of consent.
• Documented disease progression (e.g., with biopsy sample, pathology, or imaging report) occurring within 12 months (\<12 months) from the last treatment with curative intent, which meets one of the following:
• Date of the last chemotherapy administration or Date of last curative intent adjuvant radiation therapy or Date of the primary breast tumour surgery after neoadjuvant treatment, whichever occurred last
• Have not received prior chemotherapy or targeted systemic therapy for their locally advanced inoperable or metastatic recurrence Note: Prior radiation therapy for recurrent disease is permitted. There is no required minimum washout period for radiation therapy; however, patients should have recovered from the effects of radiation prior to registration.
• Measurable disease, as defined by RECIST 1.1 Note: previously irradiated lesions may be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.
• Availability of a representative FFPE tumour block (preferred) or at least 25 unstained slides collected within 12 months prior to registration Note: An FFPE block/slides will not be required for cases where tumour tissue was previously sent to the Central Laboratory for PD-L1 status testing in pre-screening following discussion with the CPI.
• Note: If a tumour sample taken within 12 months before registration is not available and a tumour biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE tumour biopsy sample may be used.
• Note: Patients with fewer than 25 unstained slides (but no fewer than 17) may be eligible following discussion with the CPI.
• Patients with an ECOG performance status 0-1 (see Appendix 1)
• Life expectancy ≥ 12 weeks
• Adequate haematologic and end-organ function, defined by the following laboratory results obtained within 7 days prior to registration:

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from study entry:
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for \> 2 weeks prior to registration to study
• Symptomatic, untreated, or actively progressing CNS metastases. Patients with a history of treated CNS lesions are eligible, provided that all of the following criteria are met:
• Measurable or non-measurable disease, per RECIST 1.1, must be present outside the CNS No history of intracranial haemorrhage or spinal cord haemorrhage Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord) There is no clinical or radiological evidence of interim progression between completion of CNS-directed therapy and the screening brain scan The patient has not received stereotactic radiotherapy within 7 days prior to registration to the study or whole-brain radiotherapy within 14 days prior to registration to the study The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable dose is permitted Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan
• Grade ≥ 2 peripheral neuropathy
• History or presence of leptomeningeal disease
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) (patients with indwelling catheters such as PleurX® are allowed)
• Uncontrolled tumour-related pain Note: Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g. bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to registration to the study. Patients should be recovered from the effects of radiation prior to registration. There is no required minimum recovery period. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g. epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy, if appropriate, prior to registration to the study.
• Uncontrolled or symptomatic hypercalcemia (\> 1.5 mmol/L ionised calcium or total calcium \>3 mmol/L or corrected serum calcium \> ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy Note: Patients who are receiving bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcaemia are eligible
• Malignancies other than TNBC within 5 years prior to registration to the study, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate ≥ 90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localised prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer)
• Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to registration, unstable arrhythmias, or unstable angina Note: Patients with a known LVEF \< 40% will be excluded Note: Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF 40-50% must be on a stable medical regimen that is optimised in the opinion of the treating physician, in consultation with a cardiologist if appropriate
• Presence of an abnormal ECG that is clinically significant in the Investigator's opinion, including complete left bundle branch block, second or third-degree heart block, evidence of prior myocardial infarction, or QTcF \> 470 ms demonstrated by at least two consecutive ECGs
• Severe infection requiring oral or IV antibiotics within 4 weeks prior to registration to the study, including but not limited to hospitalisation for complications of infection, bacteraemia, or severe pneumonia Note: patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Positive HIV test at screening
• Patients with active hepatitis B (chronic or acute; defined as having a positive HBsAg test at screening) or hepatitis C Note: Patients with past HBV infection or resolved HBV infection (defined as the presence of HBc Ab and absence of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to registration Note: Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (4)

Royal North Shore

St Leonards, New South Wales, 2065, Australia

RECRUITING

Mater Health

South Brisbane, Queensland, 4101, Australia

RECRUITING

Monash Health

Melbourne, Victoria, Australia

RECRUITING

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

RECRUITING

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Recurrence

Interventions

atezolizumab; Bevacizumab; Gemcitabine; Carboplatin

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes; Organic Chemicals

Study Officials

• Stephen Luen, Dr

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stephen Luen, Dr

CONTACT

+61385595000; stephen.luen@petermac.org

Prof Sherene Loi, Prof

CONTACT

+61385595000; sherene.loi@petermac.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 27, 2021
• First Posted: February 5, 2021
• Study Start: March 1, 2021
• Primary Completion: September 1, 2025
• Study Completion: September 30, 2025
• Last Updated: March 1, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

AU (4)