This study has been transitioned to CTIS with ID 2024-516204-42-00 check the CTIS register for the current data. The primary objective of the study is to evaluate if treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study parameters/outcome of the study:
The primary endpoint of the study is progression-free survival after two lines
of treatment (PFS2) defined as time from randomization until one of the
following (whichever occurs first):
- second objective disease progression or objective disease progression on
second-line therapy, whichever occurs first
- symptomatic deterioration on second-line therapy leading to discontinuation
of second-line therapy
- initiation of chemotherapy for breast cancer
- death
Secondary outcome
The main study has several secondary endpoints, including
- overall survival
- quality of life
- safety and tolerability
- objective response rate (ORR)
- progression-free survival after first-line therapy (PFS1)
Each substudy has its own endpoints.
Circulating tumorDNA (ctDNA) & pharmacogenetics/-kinetics (PG/PK): differences
in ctDNA and PG/PK-characteristics between responders and non-responders to
therapy; for PG/PK side effects will also be an endpoint.
Nulcear imaging (SONImage): PFS1, as defined in SONIA, correlated to
FES-/FDG-PET-characteristics.
Cognitive testing (SONIA EfFECT): the difference between baseline cognitive
score and the cognitive score after 9 months of study treatment.
Background summary
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors prevent cell cycle
progression from G1 into S phase. CDK4/6 inhibition improves progression-free
survival when added to endocrine therapy in hormone receptor positive, HER2-
negative (HR+/HER2-) advanced breast cancer. The first EMA-approved CDK4/6
inhibitor is palbociclib, an oral small molecule. Two others CDK4/6 inhibitors
are currently also approved by EMA: ribociclib and abemaciclib. The three
CDK4/6 inhibitors were investigated in very comparable phase III trials.
The PALOMA-2 trial enrolled 666 women who had not received prior systemic
treatment for advanced HR+/HER2-negative breast cancer. The trial randomly
allocated women to receive palbociclib plus letrozole or placebo plus letrozole.
Median progression-free survival (PFS) was 25 months in the palbociclib plus
letrozole arm and 15 months in the control arm. No overall survival benefit was
found and no predictive biomarker identified patients who benefit most from
adding palbociclib.
The MONALEESA-2 trial was performed with CDK4/6 inhibitor ribociclib in a
similar setting, enrolling 668 patients with advanced HR+/HER2- breast cancer
without any prior systemic treatment. The trial showed comparable results to
PALOMA-2 with a median PFS of 14.5 months in the control arm and median PFS in
the ribociclib plus letrozole arm not yet reached (hazard ratio 0.56;
P=3.29x10-6 for superiority).
Abemaciclib was investigated in a third trial, the MONARCH-3. This trial
enrolled 493 women with advanced HR+/HER2- breast cancer who had not received
prior therapy. Patients received a non-steroidal aromatase inhibitor with
either abemaciclib or placebo. The median PFS in the placebo arm was 14.7
months versus not reached in the abemaciclib arm with a hazard ratio of 0.54
and a P-value <0.001.
The PALOMA-3 trial involved 521 patients with advanced HR+/HER2- breast cancer
that had relapsed or progressed during prior endocrine therapy. Pre- and
postmenopausal women were randomly assigned to receive palbociclib and
fulvestrant or placebo and fulvestrant. Median PFS in this study was 9 months
with palbociclib plus fulvestrant and 4 months with placebo plus fulvestrant.
PALOMA-3 did not show an overall survival benefit either and also no predictive
biomarkers were found.
The MONALEESA-3 trial evaluated the effect of adding ribociclib to fulvestrant
in patients that were treatment naïve or had received up to one line of prior
endocrine therapy in the advanced setting. Median PFS in this study was 20.5
months for the ribociclib arm versus 12.8 months for the placebo arm (hazard
ratio 0.59, P<0.001). (8)
The MONARCH-2 trial was a randomized phase III study investigating the
combination of fulvestrant with CDK4/6 inhibitor abemaciclib versus fulvestrant
alone. Different from PALOMA-3, no more than one prior line of endocrine
therapy was allowed and no chemotherapy for metastatic disease was allowed. At
ASCO 2017 its results were presented. Median progression free survival was
significantly extended from 9.3 months to 16.4 months in the combination arm
(hazard ratio 0.55, P < 0.001).
Combination treatment of CDK4/6 inhibition with endocrine therapy is associated
with increased toxicity compared to endocrine therapy alone. Almost 70% of
patients experience CTCAE grade 3-4 toxicity with the combination compared to
20% with endocrine therapy alone, most importantly bone marrow suppression.
Patients with the combination in addition experience fatigue and require more
frequent hospital visits and blood checks.
The PALOMA, MONALEESA, and MONARCH trials have important implications:
• adding CDK4/6 inhibition to endocrine therapy significantly improves PFS
• many patients do well on endocrine therapy alone without CDK4/6 inhibition
• no CDK4/6 inhibitor has shown a benefit in overall survival
• benefit from CDK4/6 inhibition can be derived in first line and in subsequent
lines of treatment
• optimal positioning of CDK4/6 inhibitors in first or second line is unknown
Given the uncertain benefit in efficacy of adding CDK 4/6 inhibition to first
rather than second line endocrine treatment, the aim of this project is to
evaluate whether the sequence of an aromatase inhibitor plus CDK4/6 inhibition
in first line
followed by fulvestrant in second line is superior to the sequence of an
aromatase inhibitor in first line followed by fulvestrant plus CDK4/6
inhibition in second line.
Currently, the European Medicines Agency (EMA) has granted market access to all
three CDK4/6 inhibitors for use in first and second line. Palbociclib,
ribociclib and abemaciclib are reimbursed by the Dutch national health
insurance. Given the overlapping efficacy and safety profiles of the drugs, the
SONIA study allows investigators to choose between palbociclib, ribociclib or
abemaciclib.
Study objective
This study has been transitioned to CTIS with ID 2024-516204-42-00 check the CTIS register for the current data.
The primary objective of the study is to evaluate if treatment with a
non-steroidal aromatase inhibitor combined with CDK4/6 inhibition in first line
followed at progression by fulvestrant in second line (strategy A) improves
progression-free survival compared to treatment with a non-steroidal aromatase
inhibitor in first line followed at progression by fulvestrant combined with
CDK4/6 inhibition in second line (strategy B) in women with HR+/HER2-
metastatic breast cancer who have not received any prior systemic anti-cancer
therapy for metastatic disease
To answer several additional questions regarding the use of CDK4/6-inhibitors,
several substudies are implemented.
In the first place, we want to investigate biomarkers to help better select
patients for a certain treatment upfront. We know from previous studies that
some patients respons well to combination therapy whereas others respond very
well to endocrine monotherapy. We currently do not have any tools to predict
which patient belongs to the former category and which to the latter.
One substudy will investigate the relationship of treatment efficacy and
blood-based biomarkers: circulating tumorDNA and pharmacogenetics/-kinetics.
The substudy with nuclear imaging (SONImage) will investigate the relationship
between treatment efficacy and FES-/FDG-PET characteristics.
In addition to biomarker studies, we will also conduct a substudy that
evaluates the effects of endocrine therapy (with or without CDK4/6-inhibitors)
on cognitive functioning.
Study design
This is a nationwide, multicentre, randomized phase 3 study that compares two
strategies in the treatment of women with HR+/HER2- metastatic breast cancer
who have not received any prior systemic anti-cancer therapy for metastatic
disease. Strategy A prescribes a non-steroidal aromatase inhibitor plus CDK4/6
inhibitor in first line followed by fulvestrant in second line. Strategy B
prescribes a non-steroidal aromatase inhibitor in first line followed by
fulvestrant
plus CDK4/6 inhibitor in second line. A total of 1,050 patients will be
randomized 1:1 to receive either first line treatment with a non-steroidal
aromatase inhibitor plus a CDK4/6 inhibitor, followed at progression by
fulvestrant single agent in second line (strategy A) or first
line treatment with single agent non-steroidal aromatase inhibitor followed at
progression by fulvestrant plus a CDK4/6 inhibitor in second line (strategy B).
Patients will be stratified by site of disease (visceral versus non-visceral),
prior
endocrine treatment in (neo)adjuvant setting (yes vs. no), type of CDK4/6
inhibitor (palbociclib, ribociclib or abemaciclib), and hospital.
Intervention
Patients randomized to strategy A will receive:
first line: letrozole 2.5 mg once daily (OD) or anastrozole 1 mg
OD
in combination with
palbociclib 125 mg OD on D1- D21 of every 28-day
cycle or
ribociclib 600mg OD on D1-D21 of every 28-day
cycle or
abemaciclib 150mg twice daily (TD) continuously
second line: fulvestrant 500 mg first month D1, D15, D29 and monthly
thereafter
Patients randomized to strategy B will receive:
first line: letrozole 2.5 mg OD or anastrozole 1 mg OD
second line: fulvestrant 500 mg first month D1, D15, D29 and monthly
thereafter
in combination with
palbociclib 125 mg OD on D1-D21 of every 28-day
cycle or
ribociclib 600mg OD on D1-D21 of every 28-day
cycle or
abemaciclib 150mg TD continuously
All pre- and perimenopausal women also receive ovarian ablation or suppression.
Study burden and risks
Patients are at risk for the development of side effects associated with
endocrine treatment and CDK4/6-inhibitors. All drugs used in this trial are
FDA- and EMA-approved for this setting. In addition, patients are asked to
complete quality of life questionnaires 4 times per year.
Only in case patients provide additional informed consent, additional blood
samples will be collected for biomarker analyses and pharmacokinetic and -
genetic analyses.
Only in case patients provide additional informed consent for the nuclear
imaging substudy (SONImage), one extra visit to either the UMCG or Amsterdam
UMC-location VUMC is required for the FES-PET-scan. If no suitable FDG-PET-scan
is available, a second additional visit is required for a baseline FDG-PET.
Patients from different hospitals may be referred to either the UMCG or
Amsterdam UMC-locatie VUmc for participation in this side study. The
FES-PET-scan plus low dose CT scan will induce an extra radiation burden of
about 6.1 mSv (210 MBq injected for an average patient of 70 kilogram body
weight). An FDG-PET-scan plus low dose CT scan has a similar radiation burden.
One additional venous blood sample (6 mL) will be drawn during the FES-PET
procedure for sex hormone binding globulin (SHBG) measurement. The visit for
the FES-PET-scan takes approximately three hours; the visit for the
FDG-PET-scan takes approximately two hours. SONImage participants are also
eligible to participate in a follow-up study, SONImage 2.0. In this follow-up
study the FES-PET-scan and FDG-PET scan are repeated prior to start of second
line therapy, after progression on first line therapy.
Only in case patients provide additional informed consent for the substudy with
cognitive testing (SONIA EfFECT), they will be asked to participate in an
online neuropsychological evaluation, one time at baseline and one time after 9
months of treatment on study. Each neuropsychological evaluation will take
approximately one hour.
Moreelsepark 1
Utrecht 3511 EP
NL
Moreelsepark 1
Utrecht 3511 EP
NL
Listed location countries
Age
Inclusion criteria
Main study
1. Adult women (>= 18 years of age) with proven diagnosis of adenocarcinoma of
the breast with loco-regional recurrent or metastatic disease not amenable to
resection or radiation therapy with curative intent and for whom chemotherapy
is not clinically indicated., 2. Documentation of histologically or
cytologically confirmed diagnosis of estrogen receptor (ER) expression >10%
and/or progesterone receptor (PR) expression >10% breast cancer based on local
laboratory results. 3. Previously untreated with any systemic anti-cancer
therapy for metastatic HR+ disease, with the exception of recently started
(within 28 days of randomization) endocrine therapy. Special considerations: a)
Previous systemic treatment for locoregional recurrent disease is not an
exclusion criterion, provided that the intent was curative at the time of
systemic therapy. b) In case of previous systemic treatment for oligometastatic
disease, patients are not eligible for SONIA
Substudy ctDNA/pharmacogenetics & -kinetics:
No additional inclusion criteria
Substudy SONImage:
1. Patient is eligible and participates in the SONIA trial for ER+ advanced
breast cancer.
2. Able to give written informed consent and to comply with the SONImage
protocol.
3. Documentation of histologically confirmed diagnosis of estrogen receptor
(ER) expression >10% breast cancer based on local results. The receptor status
can be determined on the primary tumor or on a tumor biopsy of a metastatic
lesion.
Substudy SONIA EfFECT (cognitive testing):
No additional inclusion criteria.
Exclusion criteria
Main study:
1. Patients with advanced, symptomatic, visceral spread, who are at risk of
life-threatening complications in the short term. 2. Known active uncontrolled
or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal
disease. 3. Prior neoadjuvant or adjuvant treatment with a non-steroidal
aromatase inhibitor (i.e., anastrozole or letrozole) with disease recurrence
while on or within 12 months of treatment. 4. Prior treatment with any CDK4/6
inhibitor. 5. Patients treated within the last 7 days prior to randomization
with:
a. Food or drugs that are known to be CYP3A4 inhibitors
b. Drugs that are known to be CYP3A4 inducers
Substudy SONImage:
1. Contra-indication for PET imaging.
2. Use of estrogen receptor ligands (i.e. tamoxifen or fulvestrant) < 5 weeks
before FES-PET imaging.
Substudy SONIA EfFECT (cognitive testing):
No additional exlucion criteria.
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
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516204-42-00 |
| EudraCT | EUCTR2017-002334-23-NL |
| ClinicalTrials.gov | NCT03425838 |
| CCMO | NL62197.031.17 |
| OMON | NL-OMON23699 |