Primary: The co-primary objectives of this study are* to compare independently adjudicated progression-free survival (PFS) following treatment with neratinib pluscapecitabine versus lapatinib plus capecitabine in patients with HER2-positive (HER2+)…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
A: PFS is defined as disease progression (radiographic or other appropriate
modality) or death due to any cause.
o Efficacy assessment for PFS will be assessed by a blinded, independent,
central review of tumor
assessments for all patients at screening, and then after every 6 weeks from
first dose of investigational
product, regardless of treatment schedule modification (e.g., dose delay),
until documented disease
progression or death due to any cause. Progressive disease (PD) will be
independently-assessed using
RECIST v1.1.
B: Overall survival, defined as the time from randomization to death due to any
cause.
o Survival data will be collected throughout the active treatment phase and
during the long-term follow-up
phase. Survival follow-up after patient discontinuation of investigational
product will be conducted
approximately every 12 weeks to assess for survival until patient death or
withdrawal of consent.
Secondary outcome
A: Comparison of clinically relevant improvements in breast cancer patients
with respect to radiographic
changes or changes in other appropriate modalities, including (see footnote*):
o *Investigator-assessed* PFS, assessed by tumor assessments that will occur
for all patients at screening,
and then after every 6 weeks from first dose of investigational product,
regardless of treatment schedule
modification (e.g., dose delay), until documented disease progression or death
due to any cause;
o Objective response rate, defined as the proportion of patients demonstrating
either a CR or PR during the
study;
o Duration of response is measured from the time at which response criteria
were met for CR or PR
(whichever status was recorded first) until the first date of recurrence or PD
or death;
o Clinical benefit rate, defined as the proportion of patients who achieved
overall tumor response (CR or
PR) or SD for at least 24 weeks.
B: Time to intervention for symptomatic metastatic CNS disease, defined as date
of initiation of intervention or
therapy for symptomatic CNS disease determined by the investigator to be due to
CNS metastasis. This may
include brain, leptomeningeal and epidural metastases including epidural spinal
cord compression arising
from tumor growth in the epidural space.
* All of the secondary efficacy endpoints including CR, PR, and SD will be
assessed by the investigator and by the independent
review committee utilizing RECIST v1.1.
Background summary
The use of taxanes, anthracyclines, and trastuzumab early in the treatment of
HER2+ MBC has
become standard practice. In patients whose HER2 disease recurs after
adjuvant/neoadjuvant
trastuzumab therapy and in patients who initially present with advanced
metastatic HER2
disease, treatment with trastuzumab in combination with a chemotherapy regimen
is usually
prescribed. Almost all patients receiving trastuzumab alone or in combination
with other drugs
for HER2 overexpressing MBC ultimately progress. The clinical benefit of
continuing
trastuzumab after progression in the first-line metastatic setting has not been
definitively
established in prospective clinical studies. It is hypothesized that
sensitivity to trastuzumab may
be retained and that the combination of trastuzumab plus another chemotherapy
agent may be
preferable to chemotherapy alone in the second-line setting (Pusztai and Esteva
2006;
vonMinckwitz et al., 2009). This may explain the widespread acceptance and use
of trastuzumab
plus a different cytotoxic agent in the second-line setting (Love, 2004).
After multiple treatment regimens with trastuzumab and possibly lapatinib, it
is hypothesized
that the tumor may no longer be sensitive to the existing HER2 agents.
Consequently, the
continuing development of new anti-HER2 strategies is needed, particularly for
patients whose
disease has progressed on prior regimens.
This multicenter, multinational, randomized, controlled clinical study is
designed to
compare OS and independently-assessed PFS following treatment with neratinib
plus
capecitabine versus lapatinib plus capecitabine in patients with HER2+ MBC who
have received
two or more prior HER2-directed regimens in the metastatic setting.
Study objective
Primary: The co-primary objectives of this study are
* to compare independently adjudicated progression-free survival (PFS)
following treatment with neratinib plus
capecitabine versus lapatinib plus capecitabine in patients with HER2-positive
(HER2+) MBC who have
received two or more prior HER2-directed regimens in the metastatic setting.
* to compare overall survival (OS) following treatment with neratinib plus
capecitabine versus lapatinib plus
capecitabine in this population.
Secondary: The secondary objectives of this study are to compare between the
two treatment groups:
* Investigator-assessed PFS.
* Objective response rate (ORR), duration of response (DOR) and clinical
benefit (CBR) (complete response
[CR] or partial response [PR] or stable disease [SD] >=24 weeks).
* Time to intervention for symptomatic metastatic central nervous system (CNS)
disease.
* Safety (adverse events [AEs], serious adverse events [SAEs]).
* Health outcomes assessments.
Exploratory:
The exploratory objective of this study is:
* To assess the population pharmacokinetics (PK) of neratinib when
administered in combination with
capecitabine.
Study design
This is a randomized, multi-center, multinational, open-label,
active-controlled, parallel design study of the
combination of neratinib plus capecitabine versus the combination of lapatinib
plus capecitabine in HER2+ MBC
patients who have received two or more prior HER2-directed regimens in the
metastatic setting. Patients will be
randomized in a 1:1 ratio to one of the following treatment arms:
* Arm A: neratinib (240 mg once daily) + capecitabine (1500 mg/m2 daily, 750
mg/m2 twice daily [BID])
* Arm B: lapatinib (1250 mg once daily) + capecitabine (2000 mg/m2 daily, 1000
mg/m2 BID)
Patients will receive either neratinib plus capecitabine combination or
lapatinib plus capecitabine combination until
the occurrence of death, disease progression, unacceptable toxicity, or other
specified withdrawal criterion.
Patient randomization will be stratified according to:
* The number of previous HER2-directed regimens in the metastatic setting (N =
2 or N >=3).
* Geographic region (North America vs. Europe, including Israel vs. Rest of
World).
* Visceral vs. non-visceral-only disease.
* Estrogen receptor + (ER+) and/or progesterone receptor (PR+) (i.e., hormone
receptor +) versus ER- and
PR- (i.e., hormone receptor -).
Patients are anticipated to participate in the study for an average of 28
months. This includes approximately
0.5 months for screening, an estimated average of 9.5 months for the active
treatment phase, and an estimated
average of 18 months for the long-term follow-up phase. Treatment is to be
given for as long as tolerated and while
there is no disease progression. Patients who permanently discontinue treatment
will enter the long-term follow-up
phase until death or withdrawal of consent.
Intervention
Neratinib + Capecitabine Combination:
* Neratinib dosing: six 40 mg tablets (total daily dose 240 mg) orally, once
daily with food, preferably in the
morning, continuously in 21-day cycles, with no rest between cycles.
* Capecitabine dosing: 150 mg or 500 mg tablets (total dose of 1500 mg/m2
daily in 2 approximately evenly
divided doses), orally with water within 30 minutes after a meal. Doses are to
be taken daily for Days 1 to 14
of a 21-day cycle.
Lapatinib + Capecitabine Combination:
* Lapatinib dosing: five 250 mg tablets (total dose 1250 mg) orally, once
daily, 1 hour before or after breakfast,
continuously in 21-day cycles, with no rest between cycles.
* Capecitabine dosing: 150 mg or 500 mg tablets (total dose of 2000 mg/m2
daily, in 2 approximately evenly
divided doses), orally with water within 30 minutes after a meal. Doses are to
be taken daily for Days 1 to 14
of a 21-day cycle.
Study burden and risks
A summary of the information on the risks and benfits of the IMP is provided in
the current version of the Investigator's Brochure for Neratinib, section 1.
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Age
Inclusion criteria
1. Aged >=18 years at signing of informed consent.;2. Histologically confirmed MBC, current stage IV.;3. Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry [IHC] 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+). (Note: Patients who are IHC 0 or 1+ are not eligible to participate in the study). Tumor samples will be evaluated for HER2 expression by IHC (HercepTest*) and if required for gene amplification by FISH analysis (IQFISH pharmDx*).;4. Prior treatment with at least two (2) HER2-directed regimens for metastatic breast cancer. A new regimen is defined as a modification in a planned course of therapy to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new regimen also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease.;5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). ;6. Left ventricular ejection fraction (LVEF) >=50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).;7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.;8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.;9. Women of childbearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the Investigator, from the time of informed consent until 28 days after the last dose of the investigational products. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after last dose of investigational products.;10. Provide written, informed consent to participate in the study and follow the study procedures.
Exclusion criteria
1. Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2-directed tyrosine kinase inhibitor.;2. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m2 doxorubicin.;3. Any major surgery <=28 days prior to the initiation of investigational products, or received anti-cancer therapy (including chemotherapy, biological therapy, hormonal therapy, investigational agents, or other anti-cancer therapy) administered <=21 days prior to the initiation of investigational products.;4. Received radiation therapy <=14 days prior to initiation of investigational products.;5. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to randomization are eligible to participate in the study). ;6. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >=2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.;7. QTc interval >0.450 seconds or known history of QTc prolongation or Torsades de Pointes.;8. Screening laboratory assessments outside the following limits: ;Laboratory endpoint : Required limit for exclusion;8a. Absolute neutrophil count (ANC) : <1500/µL (1.5 x 10^9 /L);8b. Platelet count : <100,000/µL (<100 x 10^9/L);8c. Hemoglobin (Hb) : <8 g/dL (transfusions allowed).Transfusions must be at least 14 days prior to randomization.;8d. Total bilirubin : >1.5 x institutional upper limit of normal (ULN);8e. Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) : >3 x institutional ULN (>5 x ULN if liver metastases are present).;8f. Creatinine clearance : <50 mL/min (as calculated by Cockroft and Gault formula or Modification of Diet in Renal Disease [MDRD] formula).;9. Active infection or unexplained fever >38.5°C (>101.3°F). ;10. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or vulva; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas. ;11. Currently breast-feeding.;12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn*s disease, malabsorption, or Grade >=2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at screening).;13. Active infection with hepatitis B or hepatitis C virus.;14. Known dihydropyrimidine dehydrogenase deficiency.;15. Known hypersensitivity to 5 fluorouracil or to any component of the investigational products or compounds of similar chemical composition.;16. Unable or unwilling to swallow tablets.;17. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator*s judgment, make the patient inappropriate for this study.
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 | EUCTR2012-004492-38-NL |
| ClinicalTrials.gov | NCT01808573 |
| CCMO | NL55915.068.16 |