The purpose of this study is to compare the effectiveness of treatment Arm A and Arm B by measuring the event free survival (EFS) and pathological complete response (pCR). EFS is defined as the time from the first treatment dose that the patient…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Event Free Survival (EFS) means the length of time a patient lives with their
cancer from the point of diagnosis or start of treatment without it getting
worse. It is a good indicator of how well the treatment is working and is often
used as a standard measure in clinical trials. EFS will be defined as the time
from randomization to disease progression that: precludes definitive surgery,
results in a local or distant recurrence, results in a second primary
malignancy, or results in death due to any cause, whichever occurs first.
Pathological Complete Response (pCR) is defined as no invasive residual disease
in breast and lymph nodes, this will be determined by a local pathologist.
Secondary outcome
The secondary objectives of the study are:
- to compare Overall Survival (OS) for Arm B vs Arm C participants
- to compare Progression Free Survival (PFS) for Arm B vs Arm C
- to assess Objective Response Rate (ORR) and Complete Response Rate
- to assess Duration of Response (DOR)
- to assess Time to Response (TTR)
- to assess Time to Death or Distant Metastases (TTDM)
All of the above assessments will be performed per RECIST 1.1 using a blinded
independent committee review (BICR)
Definitions:
Progression free survival or PFS is defined as the length of time a patient
lives with their cancer from the point of diagnosis or start of treatment
without it getting worse.
Overall survival or OS is defined as the length of time a patient lives with
their cancer from the point of diagnosis or start of treatment.
Objective response rate or ORR refers to a proportion of patients with
reduction in tumour burden of a predefined amount
Duration of response or DOR is defined as the time from documentation of tumour
response to disease progression
Time to response (TTR) Time to response is defined as the time, in months, from
randomisation to the first objective documentation of partial response (PR- at
least a 30% reduction in measurable tumour size) or better assessed per BICR.
TTDM is defined as the time from the date of randomisation until the first date
of distant metastasis or death in the absence of distant metastasis. Distant
metastasis is defined as any new lesion that is outside of the radiation field
according to RECIST 1.1
Background summary
CA209-7FL is a multicentre, phase 3, double-blind study involving adult
patients with newly diagnosed, untreated breast cancer. The study will compare
treatment with either nivolumab given at the same time as chemotherapy or
chemotherapy given alone before breast cancer surgery (neoadjuvant setting),
followed by nivolumab given at the same time as endocrine treatment or
endocrine treatment given alone after breast cancer surgery (adjuvant setting).
Approximately 1200 patients will take part in this study, approximately 20 of
these will be from the Netherlands.
Breast cancer is the second leading cause of cancer-death in women after lung
cancer. Patients with localised (stage 0) disease have a five year survival
rate of about 99%. Approximately 80% of breast cancers express the estrogen
receptor (ER+), which is generally associated with a lower recurrence rate.
However, despite the availability of chemotherapy and endocrine treatment
options, this risk of recurrence seen with this breast cancer subtype persists
over time in patients, which presents an unmet need for additional treatment
strategies.
Cancer immunotherapy is based on the knowledge that tumours can be recognized
as foreign rather than as self and can be effectively attacked by an activated
immune system. Nivolumab is a type of immunotherapy drug called a monoclonal
antibody that works by blocking inhibitory signalling pathways in the immune
response. This results in stimulation of the body*s own immune system to help
attack the cancer cells. Nivolumab has demonstrated clinical activity and been
approved for the treatment of several tumour types, including melanoma,
advanced renal cell cancer and advanced non-small cell lung cancer.
This phase 3 study will evaluate clinical efficacy. Specifically, this study
will compare the pathological complete response (pCR) rate and event free
survival (EFS) rate among participants with localised invasive ER+, human
epidermal growth factor receptor 2 negative (HER2-) Breast Cancer, treated with
a combination of noeadjuvant nivolumab and chemotherapy, before surgery,
followed by adjuvant nivolumab and endocrine therapy. The pCR and EFS rate will
be compared to that among participants treated with neoadjuvant chemotherapy,
followed by surgery and adjuvant endocrine therapy, alone.
Study objective
The purpose of this study is to compare the effectiveness of treatment Arm A
and Arm B by measuring the event free survival (EFS) and pathological complete
response (pCR).
EFS is defined as the time from the first treatment dose that the patient
receives until the cancer gets worse, prevents the patient from undergoing
surgery, or results in death.
pCR is defined as the absence of disease remaining in breast and lymph node
tissues.
Study design
This is a double-blind, randomised phase 3 clinical trial of nivolumab given in
combination with chemotherapy before breast cancer surgery (neoadjuvant
setting), followed by nivolumab given in combination with endocrine treatment
given after breast cancer surgery (adjuvant setting). Subjects will undergo
screening tests and assessments to determine eligibility, and those eligible
for the study will be randomised to a treatment arm in a 2:1 ratio:
Arm A:
Nivolumab 360mg + paclitaxel for 4 treatment cycles, followed by
Nivolumab 360mg every 3 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Or
Nivolumab 360mg + paclitaxel for 4 treatment cycles, followed by
Nivolumab 240mg every 2 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Arm B:
Nivolumab Placebo + paclitaxel for 4 treatment cycles, followed by
Nivolumab Placebo every 3 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Or
Nivolumab Placebo + paclitaxel for 4 treatment cycles, followed by
Nivolumab Placebo every 2 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Patients in both treatment arms will undergo breast surgery after completing
pre-surgery treatment.
After surgery patients assigned to Arm A will receive Nivolumab 480 mg +
endocrine treatment for 7 treatment cycles (1 treatment cycle is equal to 4
weeks). Patients assigned to Arm B will receive Nivolumab placebo + endocrine
treatment for 7 treatment cycles (1 treatment cycle is equal to 4 weeks).
Randomization will be done by an automated sorting process through IVRS (a
telephone based computer system) which will assign subjects to a treatment
based on their PD-L1 status (>/ 1% or < 1%) Tumour Grade (2 or 3), Axillary
Nodal Status (+or-), Chemotherapy Anthracycline Cyclophosphamide (AC) dosing
frequency (Q3W or Q2W). This ensures that both Arms are equally balanced with
subject numbers for comparison at time of analysis, while maintaining the
integrity of the randomization itself.
A Data Monitoring Committee (DMC) will be established and meet regularly during
the study to ensure that subject safety is carefully monitored and to provide
oversight regarding safety and efficacy considerations.
Subjects will be evaluated for Event Free Survival (EFS) throughout the study.
EFS is defined as the time from randomization to disease progression that:
precludes definitive surgery, results in a local or distant recurrence, results
in a second primary malignancy, or results in death due to any cause, whichever
occurs first. Pathological Complete Response (pCR) will be performed by the
local pathologist following examination of breast and lymph node tissue removed
at the time of surgery.
Treatment will be discontinued if the subject withdraws consent, if their
cancer gets worse or if it is no longer safe for the subject to continue in the
trial.
Survival follow-up will continue for up to 10 years after the subject is
randomised.
Intervention
Subjects will undergo screening tests and assessments to determine eligibility,
and those eligible for the study will be randomised to a treatment arm in a 2:1
ratio:
Arm A:
Nivolumab 360mg + paclitaxel for 4 treatment cycles, followed by
Nivolumab 360mg every 3 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Or
Nivolumab 360mg + paclitaxel for 4 treatment cycles, followed by
Nivolumab 240mg every 2 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Arm B:
Nivolumab Placebo + paclitaxel for 4 treatment cycles, followed by
Nivolumab Placebo every 3 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Or
Nivolumab Placebo + paclitaxel for 4 treatment cycles, followed by
Nivolumab Placebo every 2 weeks + anthracycline and cyclophosphamide for a
maximum of 4 treatment cycles
Patients in both treatment arms will undergo breast surgery within 2-4 weeks,
after completing pre-surgery treatment.
Post-operative radiotherapy treatment is required if breast-conserving surgery
(BCS) is performed, per international guidelines. In the event of mastectomy,
administration of adjuvant RT will follow local clinical practice.
For patients not receiving radiotherapy, the post-surgery treatment (adjuvant
phase) will begin within 4 weeks following surgery. For patients receiving
radiotherapy, adjuvant treatment will start no later than 1 week after the
completion of radiotherapy.
Participants will return to the clinic within 7-14 days following surgery to
begin the adjuvant treatment phase. In the adjuvant phase patients assigned to
Arm A will receive Nivolumab 480 mg + endocrine treatment for 7 treatment
cycles (1 treatment cycle is equal to 4 weeks). Patients assigned to Arm B will
receive Nivolumab placebo + endocrine treatment for 7 treatment cycles (1
treatment cycle is equal to 4 weeks).
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events. Blood will also be
collected at certain visits for research purposes (PK, immunogenicity and
biomarker studies). Patients will be asked to complete questionnaires
(EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-BR23, FACIT GP5, HCRU) about their quality
of life throughout the treatment and follow-up study periods.
A breast tumour tissue sample will be collected at screening if there is no
archival tissue, or if the sample was taken too long ago (more than 60 days
prior to enrolment). Patients will be required to have a biopsy in order to
participate. An axillary lymph node biopsy will also be required if at
screening, except if there is there is no suspicion for positive axillary lymph
node(s) radiographically, or if a pathological report of suspicious lymph nodes
from the results of a fine needle biopsy or core biopsy is available. A tumour
tissue biopsy will also be performed at the time of surgery. A tumour tissue
biopsy is optional at cycle 2 day 1 and upon disease progression / recurrence.
Surgery will be performed on patients post completion of neo-adjuvant therapy.
Surgery may be either Breast Conserving Surgery or mastectomy.
Patients will undergo imaging assessment of the breast and axilla by ultrasound
and mammogram at screening, prior to surgery and annually during the follow-up
phase of the study. X-ray, CT, MRI and PET assessments will only be performed
as clinically indicated.
The frequency of visits and number of procedures carried out during this trial
would typically be considered over and above standard of care. The procedures
are carried out by trained medical professionals and every effort will be made
to minimise any risks or discomfort to the patient.
Treatment for cancer often has side effects, including some that are life
threatening. To assure an ongoing favourable risk/benefit assessment for
participants enrolled onto the study, an independent Data Monitoring Committee
(DMC) will be established to provide oversight of safety and efficacy
considerations.
New Immune system targeted therapy (immunotherapies) such as Nivolumab
potentially provide clinical benefit and improvements in the outcomes for
patients with this disease (improvement in progression free and overall
survival). However, with all experimental drugs and clinical trials, there are
known and unknown risks. Study medication and procedure related risks are
outlined in the patient information sheet in detail to ensure the patients are
fully informed before agreeing to take part in the study.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
• Participants must have histologically confirmed unilateral invasive breast
carcinoma, with the following characteristics (i, ii, iii):
i) Localized invasive breast ductal carcinoma, confirmed by the local
pathologist, that includes T1c-T2, clinical node stage (cN)1-cN2, or T3 T4,
cN0-cN2. Inflammatory breast cancer is allowed.
ii) Participants must have ER+, HER2- BC meeting below characteristics (1,2):
(1)ER+ breast cancer and with or without progesterone-receptor (determined by
central laboratory as defined in the relevant American Society of Clinical
Oncology [ASCO]-College of American Pathologists [CAP] Guidelines).
(2)HER2- breast cancer tested in a local laboratory defined as a negative in
situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+, or 2+
(determined by local laboratory as defined in the relevant ASCO- CAP
Guidelines).
iii)Participant must have Protocol-specified disease grade 2 or 3 according to
the most recent ASCO-CAP guidelines.
• Participant must have an Eastern Cooperative Oncology Group (ECOG) scale
performance status of 0 or 1.
• Participants provide tumor tissue at baseline (collected <= 60 days prior to
enrollment) and at surgery.
• Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test within 24 hours prior to the start of study treatment.
• Participants must have signed and dated an Institutional Review Board
(IRB)/Independent Ethics Committee (IEC)-approved written ICF, in accordance
with regulatory and institutional guidelines
Exclusion criteria
• Women who are breastfeeding
• Participants who are pregnant or expecting to conceive or father children
during the study, starting with the screening visit through 12 months for
patients who receive cyclophosphamide, or 7 months for patients who do not
receive cyclophosphamide, after the last dose of study treatment.
• The following Breast Cancer (BC) characteristics:
- Ipsilateral invasive BC, Inoperable BC, Multicentric BC, Bilateral invasive
BC, ipsilateral ductal carcinoma in situ treated with radiation, or
contralateral invasive BC, at any time.
- Definitive clinical or radiologic evidence of metastatic disease.
- Any of the following clinical lymph node staging: cN3, cN3a, cN3b, or cN3c
- History of ductal carcinoma in situ
- History of pleomorphic lobular carcinoma in situ
- Evidence of ER- BC
- Undergone excisional biopsy of the primary tumour and/or axillary lymph
nodes or has undergone sentinel lymph node biopsy
• Patients with >= Grade 1 peripheral neuropathy.
• Patients with an active, known, or suspected autoimmune disease. Participants
with type I diabetes mellitus, hypothyroidism only requiring hormone
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not
requiring systemic treatment, or conditions not expected to recur in the
absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other
immunosuppressive medications within 30 days of randomization. Inhaled or
topical steroids, and adrenal replacement steroid doses > 10 mg daily
prednisone equivalent, are permitted in the absence of active autoimmune
disease.
• Known human immunodeficiency virus (HIV) positive with an acquired
immunodeficiency syndrome (AIDS).
• Prior malignancy active within the previous 3 years, except for locally
curable cancers that have been apparently cured.
• Participants with serious or uncontrolled medical disorders.
• Other non-malignant systemic disease that would preclude the participant
from receiving study treatment or would prevent required follow-up.
• Active infection or chronic infection requiring chronic suppressive
antibiotics.
• Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease,
resection of the stomach or small bowel, or other disease or condition
significantly affecting gastrointestinal function.
• Any psychological, familial, sociological, or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule.
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell
co-stimulation or checkpoint pathways.
• Any treatment, local or systemic, including prior chemotherapy, Endocrine
Therapy (ET), targeted therapy, and/or radiation therapy for the currently
diagnosed BC prior to enrollment.
• Concurrent use of hormone replacement therapy, hormonal contraception or any
other estrogen-containing medication.
• Surgical axillary staging procedure prior to enrollment (with the exception
of fine-needle aspiration or core biopsy).
• Surgical excisional biopsy of primary tumour.
• Participants for whom upfront ET alone is judged clinically appropriate as
optimal neoadjuvant therapy.
• Treatment with botanical preparations (eg, herbal supplements, traditional
Chinese medicines).
• Participants who have received a live/attenuated vaccine within 30 days
before the first treatment.
• Significant cardiovascular disease, interstitial lung disease, active
pneumonitis, myocarditis, or a history of myocarditis.
• Serologic evidence of chronic HBV infection with an HBV viral load above the
limit of quantification.
• Serologic evidence of current HCV infection with an HCV viral load above the
limit of quantification.
• History of allergy or severe hypersensitivity to study drug components
• Prisoners or participants who are involuntarily incarcerated.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002469-37-NL |
| ClinicalTrials.gov | NCT04109066 |
| CCMO | NL71322.056.19 |