Biomarker discovery randomized phase IIb trial with carboplatin-cyclophosphamide versus paclitaxel with or without Bevacizumab as first-line treatment in advanced triple negative Breast cancer (TRIPLE-B study);Title after protocol amendment August 12, 2017:
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 (TRIPLE-B study)

Modified background after implementation of protocol amendment February 2017:
Triple negative breast cancer (TNBC) refers to any breast cancer that does not
express the genes for estrogen receptor (ER), progesterone receptor (PR) and
Her2/neu and is a difficult to treat molecular subtype with a poor survival.
Around 40% develops metastatic disease and these patients have a median
survival of 1 year. TNBC can be divided into at least two molecular entities;
BRStudy design: Klik voor meer iCA-like and non-BRCA-like. There are
indications that TNBC that are BRCA-like are more sensitive to bifunctional
alkylating and platinum agents than non-BRCA-like TNBCs, and relatively
resistant to taxanes. Consequently, because TNBCs in general derive substantial
benefit from taxanes, we anticipate that non-BRCA-like TNBCs are exquisitely
sensitive to taxanes. TNBCs have a relatively high mutational load resulting in
formation of neoantigens making this tumor type an attractive target for
immunomodulatory drugs. Atezolizumab, a humanized monoclonal antibody that
targets human PD-L1 has shown activity in TNBC.We hypothesize that adding
atezolizumab to paclitaxel or carboplatin-cyclophosphamide will increase the
anti-tumor effect of these regimens and possibly can obtain durable responses
in a subgroup of patients. It is unknown whether addition of atezolizumab to
first line chemotherapy in TNBC is more beneficial than adding this antibody to
a second line treatment schedule. Because of this and because of the poor
outcome of patients with advanced TNBC experiencing disease progression after
first line palliative chemotherapy, patients who were randomized to a
chemotherapy only arm in this study will be offered the opportunity to cross
over to the other chemotherapy regimen plus atezolizumab at disease
progression.

This study has been transitioned to CTIS with ID 2024-516202-39-00 check the CTIS register for the current data.

Modified objectives after implementation of protocol amendment Sept 2024:
Primary:
1. Validate the BRCA1-like test* in predicting differential PFS with first line
alkylating and platinum agents when compared to paclitaxel in TNBC

Secondary:
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 combined positive score (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 either tumor cells or 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 fist line palliative chemotherapy
in TNBC
6. Evaluate whether an alkylating-platinum regimen is more effective than
paclitaxel as first line chemotherapy regarding progression-free survival in
BRCA-like TNBC
7. Evaluate whether paclitaxel is more effective than an alkylating regimen as
first line chemotherapy regarding progression-free survival in non-BRCA-like
TNBC
8. To define whether different TNBC molecular subtypes- based on RNA -
expression analysis - predict for differential PFS 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 (CC) 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 PFS advantage 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 (PFS1+PFS2)
16. Evaluation of overall survival (OS) for all (sub)group comparisons as
pre-specified for PFS
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

Modified study design after implementation of protocol amendment February 2017:
Randomized multicenter national fase IIb study. Randomization to A I.v.
carboplatin plus cyclofosfamide.on day 1 of each 4 week cycle. At progression
paclitaxel + atezolizumab B I.v. carboplatin plus cyclofosfamide.on day 1 of
each 4 wek cycle + atezolizumab .on day 1, 15 of each 4 week cycle. At
progression: treatment up to the investigator: C I.v. paclitaxel.on day1, 8, 15
of each 4 week cycle. At progression: carboplatin plus cyclofosfamide +
atezolizumab D. I.v. paclitaxel.on day 1, 8, 15 of each 4 week cycle +
atezolizumab .on day 1, 15 of each 4 week cycle. At progression treatment up to
the investigator. 304 subjects.

Modified intervention after implementation of protocol amendment February 2017:
Trreatment with carboplatin/cyclofosfamide (group A) or paclitaxel (group C)
plus atezolizumab (groups B,D); at progression:: paclitaxel plus atezolizumab
(group A) or carboplatin/cyclofosfamide plus atezolizumab (group C) or
treatment up to the invetigator (groups B,D).

Compared to standard first line chemotherapy in metastatic breast cancer there
is hardly any additional burden when participating in this trial.
All treatment regimens, except for those with atezolizumab, are well-known and
safe cancer treatment schedules. The first results of studies with regimens
with atezolizumab, like a previous phase Ib study performed by the study team
to assess carboplatin/cyclofosfamide and atezolizumab, indicate the safety of
the combinations.
The BRCA1-test will be performed on archived tissue.
Patients should donate 9 tibes of blood prior to participation to the study, as
well as a biopsy. This should be done in an immunohub. Travel v.v. is a
consequence..
Optional tests:
1. Blood samples for biomarker study: 6 tubes once during and and after the
treatment period..
2. Tumor biopsy once during and after treatment period.
3. Storage for 15 years after the end of the study and use of remaining samples
(future research).
4. Genetic councelling: referral to clinical genetics specialist or permission
to have access to data on previous councelling.
In case patients are treated in the cross-over, blood samples and a tumor
biopsy are mandatory prior to the cross-over treatment for patients treated in
an immunohub.