The study has been designed to demonstrate whether alpelisib in combination with trastuzumab (and fulvestrant in case of HR+) shows a higher clinical benefit compared with trastuzumab in combination with chemotherapy.Some of the secondary objectives…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS: Time from randomization to objective disease progression based on the
investigator*s assessment according to the response evaluation criteria for
solid tumors (RECIST) version 1.1., or death from any cause.
Secondary outcome
OS: time from randomization to death from any cause.
OR: complete or partial response as best overall response based on the
investigator*s assessment according to RECIST version 1.1.
Safety and tolerability: adverse events (AEs) grades will be defined by the
National Cancer Institute common terminology criteria for adverse events
(NCI-CTCAE) version 5.0. AE terms will be coded according to the MedDRA
dictionary.
Background summary
Patients will be invited to participate in ALPHABET study, aimed at patients
who have PIK3CA mutated HER2+ metastatic breast cancer. HER2 is a protein
involved in cell division that is located on the surface of many cells. In
HER2+ breast cancer, the protein is highly active and can be targeted by
anti-cancer drugs. This type of therapy is called anti-HER2 therapy or HER2
blockade. Patients participating in ALPHABET will have been previously treated
with anti-HER2 drugs called trastuzumab, among others. The tumor could be
positive or negative for hormone receptors (HR). The study will assess the use
of an investigational drug (that is to say a drug that is not currently
approved for the disease scenario under study) called alpelisib (the brand name
for this drug is Piqray®). Alpelisib is known as a *PI3K inhibitor* because it
blocks the PI3K protein in cells. Alpelisib has been approved for use in some
cancer patients by the US Food and Drug Administration (FDA) and by the
European Medicines Agency (EMA) but it is not yet known whether it*s effective
in the type of breast cancer of the study population, and that is what ALPHABET
will investigate. Currently alpelisib is approved for use in combination with a
hormonotherapy drug called fulvestrant, for the treatment of postmenopausal
women and men with hormone receptor (HR)-positive, HER2-negative, locally
advanced breast cancer with a PIK3CA mutation after disease progression
following hormonal treatment as monotherapy.
Alpelisib specifically targets the protein made by an abnormal (or mutated)
PIK3CA gene, which is present in some tumors, and has been linked to cancer
growth. Research done in a lab on cells and animals suggest that PIK3CA
mutations might lead to resistance to anti-HER2 therapy. Therefore PI3K
inhibition may counteract resistance to HER2 blockade. Since resistance to HER2
blockade is a common problem in patients with advanced HER2+ breast cancer, and
it can lead to the cancer coming back or continuing to grow, there is a lot of
interest in developing strategies to overcome resistance. This could be done by
combining drugs to block PI3K, such as alpelisib, with anti-HER2 blockade. For
this reason, tumors will be tested for PIK3CA mutations, in order to determine
whether alpelisib might work.
Study objective
The study has been designed to demonstrate whether alpelisib in combination
with trastuzumab (and fulvestrant in case of HR+) shows a higher clinical
benefit compared with trastuzumab in combination with chemotherapy.
Some of the secondary objectives are to compare other efficacy measurements
and side effects, between treatment arms.
Exploratory objectives are to evaluate tumor response after progression and to
compare patients* quality of life between treatment arms. Quality of life will
be evaluated periodically by asking participants to answer a questionnaire
that will be provided by your doctor or the study staff.
Other exploratory analyses on your biological samples will be also performed
(alterations in genes, proteins, etc.) in order to identify the group of
patients who can obtain a greater benefit from the study drug due to their
biological characteristics.
Primary Objective:
To determine whether the PI3K inhibitor alpelisib + trastuzumab improve
efficacy, as measured by PFS, compared to trastuzumab + chemotherapy of
physician's choice (vinorelbine, capecitabine or eribulin) in previously
treated HER2+/HR- PIK3CA mutated advanced breast cancer patients.
To determine whether the PI3K inhibitor alpelisib + trastuzumab + fulvestrant
improve efficacy, as measured by PFS, compared to trastuzumab + chemotherapy of
physician's choice (vinorelbine, capecitabine or eribulin) in previously
treated HER2+/HR+ PIK3CA mutated advanced breast cancer patients.
Secondary Objectives
To compare additional measures of efficacy between treatment arms per cohort of
patients:
- Overall survival (OS).
- Objective response rate (ORR).
To compare safety and tolerability between treatment arms per cohort of
patients.
Study design
This is an international, multicenter, open-label, controlled phase III
randomized clinical trial in HER2+ advanced breast cancer (ABC) patients
harboring PIK3CA mutation. Appoximately 300 patients (144 in the HR- cohort and
156 in the HR+ cohort) will be enrolled. Central screening of PIK3CA mutations
on the most recent available formalin-fixed paraffinembedded (FFPE) tumor
sample is required for the purpose of eligibility. Investigators will be
encouraged to send the most recent tumor tissue, preferably from a metastatic
lesion. However, if this is not possible, archived tissue samples either from
primary tumor or metastatic lesion will be acceptable. Local screening of HR
and HER2 status is required (although there will be a central confirmation done
retrospectively). Once the screening process (locally at each site and at the
central laboratory) is completed, fully
eligible patients will be randomized in a 1:1 fashion to the control arm with
trastuzumab plus chemotherapy (CT) or to the experimental arm with trastuzumab
+ alpelisib +/- fulvestrant (depending on HR status). The two patient cohorts
defined according to HR status will be randomized separately, with
randomization in each cohort stratified by prior treatment with pertuzumab (yes
vs no) and number of prior anti-HER2 based therapy lines for MBC (<=2 vs >2). In
both cohorts patients will continue to receive their assigned treatment until
objective disease progression, symptomatic deterioration, unacceptable
toxicity, death, or withdrawal of consent, whichever occurs first.
After objective disease progression, patients in both treatment arms will be
followed until death or withdrawal of consent. In order to perform exploratory
biomarker analysis, pre-treatment tumor and sequential blood samples (at
baseline, at week 9, at the end of treatment [EOT], and at progressive disease
[PD]) will be obtained. Additionally, blood samples from approximately 100
patients (50 HR+ and 50 HR-) screened and without PIK3CA mutation will be
collected.
Intervention
Trastuzumab: 1 intravenous administration (8 mg/kg) as an initial higher dose
on day 1, and then 1 intravenous administration (6 mg/kg ) every 3 weeks, or 1
intravenous administration (4 mg/kg) as an initial higher dose on day 1, and
then 1 intravenous administration (2 mg/kg) every week, or 1 subcutaneous
administration (600 mg) every 3 weeks.
Alpelisib 300 mg by mouth once daily
If the tumor is HR+ the patient will also receive fulvestrant:
Fulvestrant: 1 intramuscular administration (500 mg) once a month with an
additional 500 mg dose 2 weeks after the initial dose. That is to say, the
patient will receive fulvestrant on days 1 and 15 of cycle 1, and then on day 1
of each subsequent cycle every 4 weeks.
Study burden and risks
Any research entails some risks, which may include side effects that may make
the patient feel sick, make the patient feel uncomfortable, develop some
specific symptoms, or may cause injuries. The patient may experience side
effects related to the study drugs during your participation in the study. We
will carefully monitor all study participants in order to detect any side
effects; nevertheless, the study team does not know all the side effects that
the study drugs could have on the patient. The medical team may give the
patient medication to help to reduce the side effects. These side effects may
be mild, moderate or severe. In some cases, these side effects may be
long-lasting or permanent, and may even be life threatening. Many side effects
can disappear when the patient stops the treatment. Furthermore, as with any
treatment, there are risks of some very rare or previously unknown side effects
appearing. The study doctor will closely monitor the patient and if some side
effects appear, will decide whether to adjust the administered doses or
discontinue the study treatment if necessary.
Avenida de los Pirineos nº 7, 1ª Planta, oficina 1-14 7
San Sebastián de los Reyes (Madrid) 28703
ES
Avenida de los Pirineos nº 7, 1ª Planta, oficina 1-14 7
San Sebastián de los Reyes (Madrid) 28703
ES
Listed location countries
Age
Inclusion criteria
1.Written informed consent prior to any specific study procedures, showing
patient willingness to comply with all study procedures. 2.Histologically or
cytologically documented locally recurrent inoperable or metastatic breast
cancer with HER2+ status based on local laboratory determination, preferably on
the most recent available FFPE tumor sample, and according to American Society
of Clinical Oncology (ASCO)/Collegue of American Pathologists (CAP)
international guidelines valid at the time of the assay. In case of discordance
in HER2+ status in different biopsies, the result from the most recent biopsy
will be used. 3.Documented HR status based on local laboratory, preferably on
the most recent available FFPE tumor sample, and according to ASCO/CAP
international guidelines valid at the time of the assay. In case of discordance
in HR status in different biopsies, the result from the most recent biopsy will
be used. HR+ will be defined as >=1% positive cells by immunohistochemistry for
Estrogen Receptor (ER) and/or Progesterone Receptor (PgR). HR- will be defined
as <1% positive cells by immunohistochemistry for both ER and PgR. For the
purpose of this study, patients with ER and PgR expression between 1 and 10%
(considered to be HR low by the most recent ASCO/CAP guidelines) will be
eligible for inclusion in the HR- cohort. 4. Patients with a PIK3CA tumor
mutation at central laboratory determination on the most representative
archival FFPE tumor sample (ie, a block with sufficient tumor surface and
cellularity) from the primary tumor or a metastatic lesion. If the tumor
analysis is not informative or inconclusive for the mutation analysis,
detection of PIK3CA mutations by the central laboratory on ctDNA extracted from
a blood sample will be allowed. 5. At least 1 prior line of anti-HER2 based
therapy for metastatic breast cancer (MBC). 6.At least 1 prior line of
trastuzumab in the metastatic setting, or in the (neo)adjuvant setting
(provided the patient relapsed while on therapy or within 6 months after
completing adjuvant trastuzumab). 7.Female or male patient is at least 18 years
of age. 8.Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
9.Patients can be either males or premenopausal/perimenopausal or
postmenopausal females. In the HR+ cohort, males and females who are not
post-menopausal must have been on a gonadotropin-releasing hormone (GnRH)
agonist (e.g. goserelin or leuprorelin) for at least 28 days prior to starting
study treatment. 10.Measurable disease or at least one evaluable bone lesion,
lytic or mixed (lytic+blastic), which has not been previously irradiated and is
assessable by computer tomography (CT)/magnetic resonance imaging (MRI) in the
absence of measurable disease according to RECIST 1.1 criteria. 11.Life
expectancy >= 12 weeks. 12.Adequate organ and marrow function defined as
follows: -Absolute neutrophil count (ANC) >= 1,500/mm3 (1.5x109/L). -Platelets >=
100,000/mm3 (100x109/L). -Hemoglobin >= 9g/dL (90g/L). -Calcium (corrected for
serum albumin) and magnesium within normal limits or <= grade 1. -Creatinine
<1.5 x upper limit of normal (ULN) or creatinine Clearance >= 35 mL/min using
Cockcroft-Gault formula (if creatinine is >=1.5 ULN). -Total bilirubin < 2 x ULN
(any elevated bilirubin should be asymptomatic at enrollment) except for
patients with Gilbert*s syndrome who may only be included if the total
bilirubin is <= 3.0 x ULN or direct bilirubin <= 1.5 x ULN. -Potassium within
normal limits, or corrected with supplements. -Aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) <= 3.0 x ULN. If patient has liver
metastasis, AST and ALT <= 5.0 x ULN. -Fasting serum amylase <= 2.0 x ULN.
-Fasting serum lipase <= ULN. -Fasting plasma glucose (FPG) < 140 mg/dL (7.7
mmol/L) and glycosylated hemoglobin (HbA1c) < 6.5%. 13.Resolution of all acute
toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE
version 5.0 grade <= 1 (except alopecia or other toxicities not considered a
safety risk for the patient at investigator*s discretion). 14.Adequate cardiac
function as defined by left ventricular ejection fraction (LVEF) of >= 50%
measured by echocardiography or multi-gated acquisition (MUGA) scans. *Please
consult the complete criteria in the protocol*
Exclusion criteria
1.Have recently received study agent(s) in any of the following scenarios:
-Fulvestrant within 12 months prior to the start of the study treatment (HR+
cohort only). -All the chemotherapy options, vinorelbine, capecitabine and
eribulin within 12 months prior to start the study treatment. Patients that
have received one or more of these chemotherapies more than 12 months prior can
receive them again as study therapy. 2.Symptomatic visceral disease or any
disease burden that makes the patient ineligible for experimental therapy per
the investigator*s best judgment. 3.Symptomatic central nervous system (CNS)
metastases. However, patients with CNS metastases who have been adequately
treated, are asymptomatic and do not require corticosteroid or anti-epileptic
medication are eligible. 4.Presence of leptomeningeal carcinomatosis. 5.Other
invasive malignancy (different from the current breast cancer) at the time of
enrollment or previous diagnosis of a completely removed malignancy within 3
years prior to randomization except for adequately treated (including complete
surgical removal) of International Federation of Gynecology and Obstetrics
(FIGO) stage I grade 1 endometrial cancer, basal or squamous cell carcinoma of
the skin, thyroid cancer limited to thyroid gland, in situ carcinoma of the
cervix, and grade 1-2 early stage bladder cancer defined as T1 or less, without
nodal involvement (N0). 6.Patients with an established diagnosis of diabetes
mellitus type I or not controlled type II (FPG >= 140 mg/dL [7.7 mmol/L] or
HbA1c >= 6.5%), or history of gestational diabetes (as per ACOG guidelines) or
documented steroid-induced diabetes mellitus. 7.Prior treatment with any mTOR,
AKT or PI3K inhibitor. 8.Patients treated within the last 7 days prior to
treatment initiation with: -Drugs that are strong inducers of CYP3A4. -Drugs
that are inhibitors of BCRP (Breast Cancer Resistance Protein). 9.Patients who
received before randomization: -Any investigational agent or other anti-cancer
therapy not listed in the protocol within 4 weeks prior to starting study
treatment (all acute toxic effects, including peripheral neurotoxicity must be
resolved to NCI-CTCAE version 5.0 grade <=1, except toxicities not considered a
safety risk for the patient at the investigator*s discretion). -Chemotherapy
within a period of time that is shorter than the cycle duration used for that
treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1
week for weekly chemotherapy). -Biologic therapy (e.g., antibodies, other than
trastuzumab which is permitted): within 4 weeks prior to starting study
treatment. -Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2
weeks prior to starting study treatment. -Corticosteroids within 2 weeks prior
to starting study treatment. -Radiotherapy within 2 weeks prior to starting
study treatment. Patients who received prior radiotherapy to >25% of bone
marrow are not eligible regardless of when it was administered. -Major surgery
within 4 weeks prior to starting study treatment and/or if patient has not
recovered from major side effects. 10.Patient has clinically significant,
uncontrolled heart disease and/or recent cardiac events. 11.Bleeding diathesis
(i.e., disseminated intravascular coagulation [DIC], clotting factor
deficiency) or long-term (> 6 months) anticoagulant therapy, other than
antiplatelet therapy and low dose coumarin derivatives, provided that the
International Normalised Ratio (INR) is less than 1.5. 12.History of clinically
significant bowel disease including abdominal fistula, or gastrointestinal
perforation. 13.Difficulties to swallow tablets, malabsorption syndrome disease
significantly affecting gastrointestinal function, resection of the stomach or
small bowel, or active inflammatory bowel disease (e.g., ulcerative diseases).
14.Known hypersensitivity to trastuzumab, alpelisib or fulvestrant or any of
their excipients. If known hypersensitivity to all three cytostatics
(vinorelbine, capecitabine and eribulin), the patient will not be eligible.
15.Active infection for hepatitis B or hepatitis C. 16.Other severe acute or
chronic medical or psychiatric condition or laboratory abnormality that may
increase the risk associated with study participation or study treatment
administration or may interfere with the interpretation of study results and,
in the judgment of the investigator, would make the patient inappropriate for
entry into this study. 17. Patients with currently documented
pneumonitis/interstitial lung disease (the chest Computed Tomography [CT] scan
performed at screening for the purpose of tumor assessment should be reviewed
to confirm that there are no relevant pulmonary complications present). 18.
Patient with liver disease with a Child Pugh score B or C. 19. Patient with a
history of acute pancreatitis within 1 year of screening or past medical
history of chronic pancreatitis. 20. Patient has a history of
Steven-Johnson-Syndrome (SJS), Erythema Multiforme (EM), Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS) or Toxic Epidermal Necrolysis (TEN).
21. Patient is nursing (lactating) or is pregnant as confirmed by a positive
serum human Chorionic Gonadotropin (hCG) test prior to initiating study
treatment. 22. Patient is a woman of child-bearing potential or a partner of a
woman of child-bearing potential, unless agreement to remain abstinent or use
single or combined non-hormonal contraceptive methods that result in a failure
rate of < 1% per year during the treatment period and for at least 7 months
after the last dose of study treatment, except for patients receiving
fulvestrant in which this period should be of at least 2 years. Abstinence is
only acceptable if it is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
post-ovulation methods) and withdrawal are not acceptable methods of
contraception. Examples of non-hormonal contraceptive methods with a failure
rate of < 1% per year include tubal ligation, male sterilization (only if he is
the sole partner and have been performed at least 6 months prior to screening),
and certain intrauterine devices. AAlternatively, a combination of two barrier
methods (e.g., a condom and a cervical cap) is also acceptable.*Barrier methods
must always be supplemented with the use of a spermicide. Male participants
must not donate sperm during study and up to the time period specified above.
*Please consult the complete criteria in the protocol*
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 | EUCTR2020-005639-65-NL |
| ClinicalTrials.gov | NCT05063786 |
| CCMO | NL81153.068.22 |