In the current phase 2 study we will investigate the efficacy of the combination of fulvestrant and alpelisib directly after progression on 1st or 2nd line therapy with fulvestrant with or without a CDK 4/6 inhibitor in patients with HR+HER2-…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- to determine Progression-free survival (PFS), defined as time from study
enrollment to disease progression or death from any cause, with censoring when
fulvestrant and alpelisib are stopped and another treatment is initiated
without confirmed disease progression.
Secondary outcome
- to determine *on treatment* Progression-free survival (PFS), defined as time
from study enrollment to disease progression or death from any cause, with
censoring when fulvestrant and alpelisib are stopped earlier than disease
progression;
- to determine the Objective Response Rate, described as complete response (CR)
or partial response (PR);
- to determine the Clinical Benefit Rate, described as stable disease (SD), PR,
or CR;
- to determine the Duration of Response (DoR);
- to evaluate safety and tolerability;
- to determine timing and severity of alpelisib-induced hyperglycaemia;
- to determine risk factors for alpelisib-induced hyperglycaemia;
- to assess Quality of Life (QoL);
- to evaluate Patient Reported Outcome Measures (PROMs);
- to compare PFS in patients with the 11 most frequent activating PIK3CA
mutations with PFS in patients with unselected activating PIK3CA mutations
(including rare mutations);
- to determine Overall Survival (OS);
- to determine pharmacokinetics of alpelisib.
Background summary
In the pivotal SOLAR-1 study alpelisib, a PI3K α-specific inhibitor, added to
fulvestrant led to a median progression free survival (PFS)-benefit of 5.3
months (11.0 vs. 5.7 months; HR 0.65; 95% CI, 0.50- 0.85; p<0.001) compared to
fulvestrant monotherapy in patients with PIK3CAmutated, hormone receptor (HR)
positive, human epidermal growth factor receptor 2 (HER2) negative advanced
breast cancer (Andre et al , 2019). In this study men and postmenopausal women
were included who relapsed or progressed on or after adjuvant or palliative
treatment with an aromatase inhibitor (AI) and had not received fulvestrant
previously. Only ~ 6% of the patients had already received a Cyclin-Dependent
Kinase 4/6-(CDK4/6) inhibitor. Around half of the patients was treated in first
and the other half in second line.
In the current phase 2 study we will investigate the efficacy of the
combination of fulvestrant and alpelisib directly after progression on 1st or
2nd line therapy with fulvestrant with or without a CDK 4/6 inhibitor in
patients with HR+HER2- advanced breast cancer with tumors harboring an
activating PIK3CA mutation. Primary endpoint is PFS. The aim is to determine a
clinically meaningful median PFS of at least six months.
Study objective
In the current phase 2 study we will investigate the efficacy of the
combination of fulvestrant and alpelisib directly after progression on 1st or
2nd line therapy with fulvestrant with or without a CDK 4/6 inhibitor in
patients with HR+HER2- advanced breast cancer with tumors harboring an
activating PIK3CA mutation. Primary endpoint is PFS. The aim is to determine a
clinically meaningful median PFS of at least six months.
Study design
phase 2 study
Intervention
Alpelisib 300mg once daily (may be reduced to 1dd250 or 1dd200mg in case of
toxicity) + fulvestrant 300mg 1x/four weeks.
Study burden and risks
Since extensive pre-clinical and clinical studies have been performed, effect
and possible toxicities of alpelisib are rather predictable. The toxicities are
described in the protocol.
There is growing experience with toxicity management from previous and ongoing
clinical studies. Data from these studies show that common toxicities are
generally manageable by common clinical practices. Furthermore, alpelisib does
not inhibit PIK3CA-pathway irreversibly and half-time is only 8-9 hours, so if
severe toxicity were to occur, the effects will likely be reversible within
days. In our opinion, the burden and risks are justified by the potential
benefits. We consider the risk of partaking in the study to be low, especially
since the treatment given in the study is also commercially available for this
population, and applied. Hence, patients participating in the study will not be
subject to any additional risk. Patients in the study will be carefully
assessed for any toxicities, and given instructions on how to seek medical
support when necessary.
The potential benefit (PFS increase) justifies these risks for this group of
patients with advanced breast cancer, status after two lines of systemic
treatment.
Godebaldkwartier 363
Utrecht 3511 DT
NL
Godebaldkwartier 363
Utrecht 3511 DT
NL
Listed location countries
Age
Inclusion criteria
* Adult women and men (>= 18 years of age) with proven diagnosis of
adenocarcino-ma of the breast with locoregional recurrent or metastatic disease
not amenable to resection or radiation therapy with curative intent and for
whom chemotherapy is not clinically indicated
* Estrogen receptor (ER) expression >10% and/or progesterone receptor (PR)
expression >10% breast cancer based on local la-boratory results. Tumor must be
HER2- as defined by ASCO-CAP guidelines
* Patients must have progressed on fulvestrant as a preceding treatment line
(as first or second line therapy)
* Previous treatment with a CDK4/6 inhibitor in the advanced setting
* The presence of an activating PIK3CA mutation
* Evaluable disease* as defined per RECIST v.1.1
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Exclusion criteria
* Patients with advanced, symptomatic, visceral spread, who are at risk of
life-threatening complications in the short term
* Known active uncontrolled or symptomatic CNS metastases, carcinomatous
meningitis, or leptomeningeal disease as indicated by clinical symptoms,
cerebral edema, and/or progressive growth
* Prior treatment with an PI3K /AKT/mTOR inhibitor
* Prior treatment with chemotherapy in the advanced setting
* (prior) use of oral SERD in any setting
* Type 1 diabetes or uncontrolled type 2 diabetes (Hba1C > 68 mmol/mol)
* Clinically significant, uncontrolled heart disease and/or recent cardiac
events
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 | EUCTR2021-004191-33-NL |
| ClinicalTrials.gov | NCT05392608 |
| CCMO | NL78749.031.21 |