Primary ObjectivesSafety run-in Part 1:To confirm the recommended dose of alpelisib in combination with trastuzumab and pertuzumab for Part 2.Double-blind, randomized, placebo-controlled Part 2:To determine whether treatment with alpelisib in…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
For Part 1, the incidence of dose-limiting toxicities during the first 6 weeks
of treatment (i.e. 2 cycles) is the primary endpoint.
For Part 2, PFS, as assessed by the local radiologists/investigators using
RECIST 1.1 criteria will be the primary endpoint.
Secondary outcome
Secondary endpoint Part 1 & 2:
• Safety: Incidence, type, and severity of adverse events per Common
Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria including
changes in laboratory values, vital signs, liver assessments and cardiac
assessments
• Tolerability: dose interruptions, reductions, dose intensity, and duration of
exposure for all drug components
• Summary statistics of alpelisib concentrations by timepoint and dose level
Additional secondary endpoints Part 2:
• ORR with confirmed response, CBR with confirmed response, DOR with confirmed
response, and TTR based on local radiology assessments and using RECIST 1.1
criteria.
• Change from baseline in the FACT-B Trial Outcomes Index (TOI) score. Time to
5-point definitive deterioration in the TOI score of the FACT-B
• PFS based on local radiology assessments and using RECIST 1.1 criteria for
patients by PIK3CA mutation status assessed in ctDNA at baseline
• Time to definitive deterioration of the ECOG performance status from
baseline.
Background summary
Breast cancer (BC) is the most common cancer in women and the second most
common cancer overall, with more than two million new cases predicted for 2018
worldwide (Bray et al 2018). Among men, BC is much less common, accounting for
<1% of all cases (Siegel et al 2018). Breast cancer is the second leading cause
of cancer-related death globally, with 626,679 deaths predicted for 2018 (Bray
et al 2018).
Of the new breast cancers diagnosed worldwide each year, approximately 20%-25%
are human epidermal growth factor receptor 2 neu (HER2) positive (Jemal et al
2011).
The standard approach to management of men and women with advanced (metastatic
or loco regionally recurrent) HER2-positive BC includes HER2-targeted therapies
trastuzumab and pertuzumab with a taxane. This regimen, in the first-line
setting, has been shown, in the CLEOPATRA study, to improve median
progression-free survival (PFS) by 6.3 months (from a median PFS of 12.4 months
for subjects treated with placebo plus trastuzumab plus docetaxel to a median
of 18.7 months in subjects treated with pertuzumab plus trastuzumab plus
docetaxel, HR=0.62, p<0.001) and median OS by 15.7 months (from a median OS of
40.8 months to 56.5 months, respectively, HR=0.68, p<0.001) (Baselga et al
2012, Swain et al 2015). In the subgroup of subjects whose tumors harbored a
PIK3CA mutation, the benefit of adding pertuzumab and trastuzumab to a taxane
was equally demonstrated, but the median PFS was observed to be shorter than
whose tumors expressed wild-type in both the pertuzumab-treated group (12.5
months vs. 21.8 months) and placebo-treated group (8.6 months vs. 13.8 months)
(Baselga et al 2014).
Therefore, despite the improvement in both PFS and OS with the addition of
pertuzumab and trastuzumab to the standard chemotherapy backbone, this
treatment regimen is limited by disease refractoriness and recurrence
particularly in patients whose tumors harbor a PIK3CA mutation.
Study objective
Primary Objectives
Safety run-in Part 1:
To confirm the recommended dose of alpelisib in combination with trastuzumab
and pertuzumab for Part 2.
Double-blind, randomized, placebo-controlled Part 2:
To determine whether treatment with alpelisib in combination with trastuzumab
and pertuzumab prolongs PFS compared to placebo in
combination with trastuzumab and pertuzumab in adult patients wi th
HER2-positive advanced breast cancer with a PIK3CA mutation
Secondary Objectives
Safety run-in Part 1
To determine the safety and tolerability of alpelisib in combination with
trastuzumab and pertuzumab
To characterize exposure of alpelisib when administered in combination with
trastuzumab and pertuzumab
Double-blind, randomized, placebo-controlled Part 2:
To determine whether treatment with alpelisib in combination with trastuzumab
and pertuzumab prolongs OS compared to placebo in
combination with trastuzumab and pertuzumab in adult patients with
HER2-positive advanced breast cancer with a PIK3CA mutation
To assess safety and tolerability
To assess additional efficacy parameters
To characterize exposure of alpelisib, when administered in combination with
trastuzumab and pertuzumab
To evaluate patient-reported outcomes of alpelisib in combination with
trastuzumab and pertuzumab compared to placebo with trastuzumab
and pertuzumab *
To evaluate the association between PIK3CA mutation status as measured in ctDNA
at baseline with PFS upon treatment with alpelisib
To evaluate alpelisib in combination with trastuzumab and pertuzumab compared
to alpelisib matching-placebo with trastuzumab and
pertuzumab with respect to time to deterioration of Eastern Cooperative
Oncology Group (ECOG) performance status
Study design
This is a two-part study. Part 1, the safety run-in, is an open-label study
designed to confirm the recommended phase 3 dose (RP3D) of alpelisib in
combination with approved doses of trastuzumab and pertuzumab. Following
confirmation of the RP3D in Part 1, Part 2 will be initiated. Part 2 is a
double-blind, randomized, placebo-controlled, international, multicenter Phase
III trial designed to evaluate the efficacy and safety of alpelisib in
combination with trastuzumab and pertuzumab compared to alpelisib
matching-placebo in combination with trastuzumab and pertuzumab as maintenance
therapy following pre-study induction treatment in adult men and women with
HER2-positive advanced BC whose tumor harbors a PIK3CA mutation.
Intervention
Treatment with trastuzumab and pertuzumab with or without alpelisib.
Study burden and risks
Risk: potential side effects of study treatment
Burden:
Pre-screening: a tumor sample will be taken for PIK3CA mutation testing after
signing the molecular screening consent for central testing
The study visits are divided into cycles. Each cycle is 3 weeks (21 days). The
number of cycles performed will depend on the status of the patient*s cancer.
Study participation will include hospital/clinical visits, physical
examinations, and taking blood and other samples.
The patient will come to the study doctor*s clinic 3 times during cycle 1; then
2 times during cycles 2, and then 1 time (or more if needed) for the rest of
the cycles until the patient discontinues the study treatment. Each visit takes
approximately half a day to one full day, depending on how many blood samples
need to be collected.
After the patient discontinues study treatment, he/she will be followed for
safety, for cancer status (if needed), and survival.
• Physical examination: At cycle 1 day 8 and 15, cycle 2 day 1 and Day 1 of
every subsequent cycle (every 3 weeks).
• Performance status: At cycle 2 day 1 and Day 1 of every subsequent cycle
(every 3 weeks).
• Weight: will be taken at Day 1 of every cycle
• Vital signs: At cycle 1 day 1 and day 15, cycle 2 day 1 and Day 1 of every
subsequent cycle (every 3 weeks).
• Electrocardiogram (ECG): At Cycle 1 Day 1 and then every 12 weeks.
• Cardiac imaging (Multigated Acquisition scan (MUGA), Echocardiogram or
cardiac MRI): At cycle 1 day 1 and every 9 weeks for the first 18 months and
then every 12 weeks.
• Quality of Life Questionnaires: We want to know more about the patient*s
overall health and quality of life, pain and other symptoms. We will ask the
patient to complete the surveys every 9 weeks during the first 18 months
followed by every 12 weeks thereafter. The patient will provide his/her answers
on a tablet computer, provided by Novartis, during study visits. This should
take about 15 to 30 minutes each time. And 3 times the QOL questionnaires after
disease progression is established: week 9, week 18 and week 27
• Imaging examinations during the study:
• CT or MRI of your chest, pelvis and abdomen will be performed every 9 weeks
(for the first 18 months), and then every 12 weeks.
• Images of brain, bones, skin, or any other sites where the patient has
cancer may be taken if needed, at the same times as above.
Haaksbergweg 16
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Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
• Subject is an adult >= 18 years old, with HER2-positive advanced breast
cancer.
• Applies only to Part 2: Subject has a PIK3CA mutation(s) present in tumor
tissue prior to enrollment, as determined by a Novartis designated central
laboratory.
• Subject has received pre-study induction therapy with up to and including 6
cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab
and pertuzumab. A minimum of 4 cycles of taxane is permitted if discontinuation
was due to toxicity.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status 0
or 1.
• Adequate bone marrow and organ function (based on central lab)
Exclusion criteria
• Subject with inflammatory breast cancer at screening.
• Subject is concurrently using other anti-cancer therapy, with the exception
of endocrine therapy in HR+ subjects.
• Subject has received radiotherapy <= 4 weeks or limited field radiation for
palliation <= 2 weeks prior to randomization, and who has not recovered to grade
1 or better from related side effects of such therapy (with the exception of
alopecia).
• Subject has a concurrent malignancy or malignancy within 3 years of study
entry, with the exception of: See excl. crit 7, page 42.
• Subject has central nervous system (CNS) involvement.
• Subject with evidence of disease progression during the pre-study induction
therapy and prior to first dose of alpelisib (or alpelisib/alpelisib
matching-placebo for Part 2)
• Subject with an established diagnosis of diabetes mellitus type I or not
controlled type II based on FPG and HbA1c (see inclusion criteria 7).
• Subject has impairment of gastrointestinal (GI) function or GI disease that
may significantly alter the absorption of the study drugs
• Subject has a known history of acute pancreatitis within 1 year of screening
or past medical history of chronic pancreatitis.
• Uncontrolled hypertension. See excl crit 13, page 42
• Subject has any other concurrent severe and/or uncontrolled medical condition
(e.g., chronic active hepatitis, severe hepatic impairment, etc.).
• Subject has currently documented pneumonitis/interstitial lung
• Subject has clinically significant, uncontrolled heart disease and/or recent
cardiac events
• Subject has a history of severe cutaneous reaction. See excl crit 17, page 43
• Prohibited medication. See protocol page 41-43 for details.
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 | EUCTR2019-002741-37-NL |
| ClinicalTrials.gov | NCT04208178 |
| CCMO | NL72468.068.20 |