Biomarker discovery randomized phase IIb trial with carboplatin-cyclophosphamide versus paclitaxel with or without atezolizumaB as first-line treatment in advanced triple negative Breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BOOG Study Center B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Oct 2013 → ongoing

Decision date (initial)

2024-11-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516202-39-00

EudraCT number

2013-001484-23

ClinicalTrials.gov

NCT01898117

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Safety, Efficacy, Therapy

Validate the BRCA1-like test in predicting differential progression free survival (PFS) according to RECIST v1.1 definitions for measurable and non-measurable disease with first line alkylating and platinum agents (± antibody add-on) when compared to paclitaxel (± antibody add-on) in TNBC

Secondary objectives 19

1. Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1)
2. Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide for patients with PD-L1 positive tumors defined as CPS 10 or higher (PFS1)
3. Test whether the addition of atezolizumab to chemotherapy will result in more objective responses and a higher proportion of patients who are free of progression at 6 months and at 12 months
4. Analyze whether PD-L1 (immunohistochemistry) in tumor infiltrating immune cells predicts for potential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
5. Analyze whether intratumoral CD8 and tumor infiltrating lymphocytes (TIL) predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC
6. Evaluate whether an alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS in BRCA1-like TNBC
7. Evaluate whether paclitaxel is more effective than an alkylating regimen as first line chemotherapy regarding PFS in non-BRCA1-like TNBC
8. To define whether different TNBC molecular subtypes (based on RNA–expression analysis) predict for benefit of atezolizumab added to first line palliative chemotherapy in TNBC
9. To define whether pretreatment LDH level predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC
10. To define biomarkers that can predict for a PFS advantage of carboplatin-cyclophosphamide as first line palliative chemotherapy in TNBC
11. To define biomarkers that can predict for a PFS advantage of paclitaxel as first line palliative chemotherapy in TNBC
12. To define biomarkers that can predict for a benefit of addition of atezolizumab to first line palliative chemotherapy in TNBC
13. Evaluation of PFS after cross-over to the other chemotherapy regimen with atezolizumab (PFS2)
14. Evaluation of ORR, proportion of patients that is free of progression at 6 months and at 12 months after cross-over to the other chemotherapy regimen with atezolizumab
15. Evaluate whether addition of atezolizumab to chemotherapy in first line is more beneficial than when added in second line
16. Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS and evaluation of overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR) for all atezolizumab-related questions
17. Evaluate clinically relevant toxicity of all study regimens
18. Evaluate preliminary efficacy by PFS and OS in subgroups of patients treated before amendment 3 with carboplatin-cyclophosphamide or paclitaxel with or without bevacizumab
19. Evaluate putative predictive potential of BRCA1-like status in various subgroups defined by treatment regimen received before amendment 3.

Conditions and MedDRA coding

Metastatic breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Histologically confirmed triple negative metastasized or locally advanced incurable breast cancer
2. Histological confirmation of triple negative breast cancer of a metastatic lesion is recommended
3. Histological or cytological confirmation of metastatic breast cancer is required in case of normal CA 15.3 levels
4. Primary tumor or metastasis tissue sent to NKI-AVL for BRCA1-like testing
5. Pretreatment histological biopsy of a metastatic lesion for the translational research questions (tumor tissue from bone metastases cannot be used)
6. No previous cytotoxic therapy for metastatic disease
7. Disease-free interval of at least 12 months after completion of (neo)adjuvant paclitaxel or (neo)adjuvant platinum compound
8. Disease-free interval of at least 6 months after completion of (neo) adjuvant docetaxel
9. Measurable or evaluable disease according to RECIST V1.1
10. WHO performance status of 0 or 1

Exclusion criteria 17

1. Receptor conversion to hormone receptor positive (defined as ≥ 10% ER positive tumor cells) or HER2 positive
2. Other antitumor therapy within the previous 21 days, with the exception of endocrine therapy. The patient should have stopped any endocrine therapy before start study treatment.
3. Radiotherapy with palliative intent within the previous 7 days before start study medication
4. Known CNS disease except for treated brain metastases
5. Pre-existing peripheral neuropathy > grade 1 (NCI-CTC AE (version 4.03) at inclusion)
6. Use of denosumab is not allowed
7. Severe infection in the last 4 weeks
8. Antibiotics in the last 2 weeks
9. History of autoimmune disease
10. Prior allogeneic stem cell or solid organ transplantation
11. History of lung diseases such as idiopathic pulmonary fibrosis, pneumonitis
12. An infection requiring parenteral antibiotic
13. Positive test for hepatitis B, C or HIV
14. Active tuberculosis
15. Live, attenuated vaccine within 4 weeks prior to randomization
16. Prior treatment with anti cancer vaccins or immune checkpoint blockade therapies, including anti-CTLA-4, CD137 agonist, OX40 agonist, anti-PD-1, or anti-PD-L1 therapeutic antibodies
17. Treatment with systemic immunostimulatory agents, systemic corticosteroids or other systemic immunosuppressive medications

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Interaction test of BRCA1-like status vs. treatment (CC vs. paclitaxel (both arms with or without atezolizumab or bevacizumab (patients before amendment 3)) and PFS according to RECIST v1.1 definitions for measurable and non-measurable disease 1-3.

Secondary endpoints 19

1. Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide for patients with PD-L1 positive tumors defined as CPS 10 or higher (PFS1)
2. Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1)
3. Test the benefit of the addition of atezolizumab to chemotherapy using objective response rate (ORR), proportion of patients free of progression at 6 months and at 12 months, all according to RECIST v1.1 definitions (see also appendix F) 1-3.
4. Overall- survival (OS) benefit of the addition of atezolizumab versus no atezolizumab to first line palliative chemotherapy. OS is measured from the day of randomization to the occurrence of death of any cause.
5. Determine PFS and OS regarding the efficacy of the two different first line chemotherapeutic regimens, regardless of antibody add-on yes or no, in the whole study group, and in the BRCA1-like and non-BRCA1-like TNBC subgroups separately.
6. Evaluate whether a PFS/ORR/OS difference exists between efficacy of atezolizumab added to chemotherapy in BRCA1-like TNBC and in non-BRCA1-like TNBC, regardless of chemotherapy regimen
7. Evaluate whether a PFS/ORR/OS difference exists between efficacy of atezolizumab added to chemotherapy in BRCA1-like TNBC and non-BRCA1-like TNBC, stratified by chemotherapy regimen
8. Evaluate whether an alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS/OS in BRCA1-like TNBC
9. Evaluate whether paclitaxel is more effective than an alkylating regimen as first line chemotherapy regarding PFS/OS in non-BRCA1-like TNBC
10. Define whether PD-L1 status predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC; test association between PD-L1 status and ORR, proportion of patients free of progression at 6 months and at 12 months stratified by chemotherapy regimen
11. Define whether tumor intratumoral CD8 and tumor infiltrating lymphocytes (TIL) predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC; test the association between intratumoral CD8 (cut off to be determined) and ORR, proportion of patients free at progression at 6 and 12 months stratified by chemotherapy regimen.
12. Determine whether certain molecular TNBC subtypes (based on RNA-expression analysis) are predictive for benefit of atezolizumab to first line chemotherapy using ORR, proportion of patients free of progression at 6 months and at 12 months
13. Discovery of predictive biomarkers for benefit of atezolizumab added to first line palliative chemotherapy in TNBC using ORR, proportion of patients free of progression at 6 months and at 12 months
14. To define whether pretreatment LDH level (cut off to be determined) predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC using ORR, proportion of patients free of progression at 6 months and at 12 months
15. Exploratory analysis to define biomarkers that can predict for a PFS/OS advantage of carboplatin-cyclophosphamide as first line palliative chemotherapy in TNBC
16. Exploratory analysis to define biomarkers that can predict for a PFS/OS advantage of paclitaxel as first line palliative chemotherapy in TNBC
17. Evaluation of progression free survival (PFS2)/ORR and proportion of patients free of progression at 6 months and 12 months after cross-over to the other chemotherapy regimen with atezolizumab
18. Evaluate whether addition of atezolizumab to chemotherapy in first line is more beneficial than when added in second line
19. Clinically relevant toxicity of all study regimens according to NCI CTCAE v4.03

Investigational products

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

Test 6

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BOOG Study Center B.V.

Sponsor organisation

BOOG Study Center B.V.

Address

Moreelsepark 1

City

Utrecht

Postcode

3511 EP

Country

Netherlands

Scientific contact point

Organisation

BOOG Study Center B.V.

Contact name

BOOG Study Center

Public contact point

Organisation

BOOG Study Center B.V.

Contact name

BOOG Study Center

Third parties 2

Locations

1 EU/EEA country · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 8 files

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

Application history

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