The primary objective of the study is to compare the efficacy of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC patients naive to ALK inhibitors, as evidenced by PFS.The secondary objectives of the study are:1. To…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
longaandoeningen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS, as assessed by the BIRC, per RECIST v1.1 (Eisenhauer et al, 2009)
Secondary outcome
1. Confirmed ORR, as assessed by the BIRC, per RECIST v1.1
2. Confirmed intracranial ORR as assessed by the BIRC
3. Intracranial PFS, as assessed by the BIRC
4. OS
5. Duration of response, as assessed by the BIRC
6. Time to response, as assessed by the BIRC
7. Disease control rate, as assessed by the BIRC
8. Safety and tolerability
9. Change from baseline scores in global health status/quality of life (QOL),
assessed with the EORTC QLQ-C30 (v3.0) and time-to-deterioration in dyspnea
assessed with the EORTC QLQ-LC13 (v3.0)
Background summary
Activating gene rearrangements in anaplastic lymphoma kinase (ALK) have been
identified as driver mutations in approximately 2% to 7% of patients with
non-small cell lung cancer (NSCLC) (Kwak et al, 2010; Wong et al, 2009).
Crizotinib (XALKORI® USPI, Pfizer, Inc.) has demonstrated clinical efficacy in
ALK+ NSCLC. Results from a phase 1 study and a phase 2 single-arm study of
crizotinib
demonstrated objective response rates (ORRs) of 61% and 50%, respectively
(XALKORI® USPI, Pfizer, Inc.). These 2 studies served as the basis for
accelerated approval of crizotinib for treatment of ALK+ advanced NSCLC in the
United States (US) in 2011 and conditional marketing authorization in the
European Union (EU) in 2012. The efficacy of crizotinib in ALK+ NSCLC patients
has also been investigated in a randomized active-control study against
chemotherapy (pemetrexed or docetaxel) (XALKORI® USPI, Pfizer, Inc.). A
statistically significant improvement in progression-free survival (PFS) was
observed in patients treated with crizotinib compared with patients treated
with chemotherapy (hazard ratio, 0.49; 95% CI: 0.37 to 0.64; p<0.001). A median
PFS of 7.7 months was seen with crizotinib versus 3.0 months with chemotherapy.
Regular approval for crizotinib was granted by the US Food and Drug
Administration (FDA), on the basis of this study, in 2013. In a separate
randomized active-control study of crizotinib against pemetrexed-platinum
doublet chemotherapy in patients with advanced previously untreated non-squamous
ALK+ NSCLC, median PFS was 10.9 months in the crizotinib arm and 7.0 months in
the chemotherapy arm (hazard ratio for progression or death with crizotinib,
0.45; 95% CI: 0.35 to 0.60; p<0.001) (Solomon et al, 2014). Currently, two
tests are FDAapproved for detection of ALK+ NSCLC: the Vysis® ALK Break-Apart
fluorescence in situ hybridization (FISH) Probe Kit (Abbott Molecular, Inc.)
and the Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Inc.), an
immunohistochemistry (IHC) assay.
Although crizotinib is an effective treatment for ALK+ NSCLC, almost half (39%
and 52%, respectively) of ALK+ NSCLC patients in the two trials that supported
its accelerated approval failed to achieve a response. For those patients who
did respond, the benefit was relatively short with a median duration of
response of 11 months (XALKORI® USPI, Pfizer, Inc.). In many patients, loss of
response to crizotinib manifests as systemic progression, but in some patients
the disease progresses only within the brain, possibly as a result of low
central nervous system (CNS) penetration of crizotinib (Camidge et al, 2012;
Costa et al, 2011).
The underlying reason for failure to achieve a response to crizotinib (primary
resistance) is difficult to identify, but suboptimal potency of the agent
against the targeted oncogene could be a contributing factor. The mechanisms
underlying loss of response (secondary or acquired resistance) to crizotinib
are becoming more clear (Camidge et al, 2012). Emerging data suggest that an
important acquired resistance mechanism is the emergence of point mutations in
the kinase domain of ALK (Katayama et al, 2012). Mutations that confer
resistance to crizotinib (such as the gatekeeper mutant L1196M, as well as
L1152R, G1269A, S1206Y, F1174L, D1203N, C1156Y, T1151Tins, and G1202R
mutations) may act by reducing the
binding affinity of crizotinib to ALK (Bang, 2012).
In some patients, loss of response to crizotinib may also have a pharmacologic
basis, with inadequate drug exposure resulting from dose modifications, or
changes in drug metabolism or transport over time. In all of these scenarios, a
rational approach to overcoming resistance is the use of a more potent ALK
inhibitor with a broader therapeutic window that suppresses the emergence of
resistance mutations in ALK
and that can also achieve deep and prolonged target inhibition both
systemically and in the CNS (for patients with brain metastases).
Brigatinib is a novel, synthetic, orally-active ALK tyrosine kinase inhibitor
(TKI) discovered and developed at ARIAD Pharmaceuticals, Inc. Brigatinib has
demonstrated potent in-vitro inhibitory activity against activated ALK
(approximately 10-fold more potent than crizotinib) and pan-inhibitory activity
against all 17 ALK resistance mutants identified to date, including the L1196M
gatekeeper mutation and the G1202R mutation.
Study objective
The primary objective of the study is to compare the efficacy of brigatinib to
that of crizotinib in ALK+ locally advanced or metastatic NSCLC patients naive
to ALK inhibitors, as evidenced by PFS.
The secondary objectives of the study are:
1. To compare the efficacy of brigatinib to that of crizotinib, as evidenced by
confirmed ORR, time to/duration of response, disease control rate (DCR), and
Overall Survival (OS)
2. To compare the efficacy in the CNS of brigatinib to that of crizotinib, as
evidenced by intracranial response and intracranial PFS in those patients
with intracranial CNS metastases at baseline
3. To assess the safety and tolerability of brigatinib in comparison with
crizotinib
4. To determine pharmacokinetic (PK) parameters of brigatinib through
population PK modeling
5. To assess patient-reported symptoms and health-related quality of life
(HRQoL) with the European Organisation for Research and Treatment of
Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 (v3.0) and its lung
cancer module, QLQ-LC13 (v3.0) in patients treated with brigatinib compared to
those treated with crizotinib
The exploratory objectives of the study are:
1. To assess confirmed ORR on brigatinib in patients who crossover to
brigatinib from Arm B (crizotinib); and to assess PFS, from the first dose of
brigatinib, in patients who crossover to brigatinib from Arm B
2. To explore the relationship of brigatinib exposure with both efficacy and
safety
3. To explore the molecular determinants of efficacy and safety for brigatinib
and crizotinib
Study design
Patients will be randomized to receive brigatinib or crizotinib in a 1:1
fashion. Patients will be stratified by the presence of intracranial CNS
metastases at baseline (Yes versus No) and prior chemotherapy use for locally
advanced or metastatic disease (Yes versus No). For the purposes of
stratification, prior chemotherapy is defined as completion of *1 full cycle of
chemotherapy in the locally advanced or metastatic setting.
Arm A (brigatinib):
Brigatinib will be administered orally at a dose of 90 mg QD for 7 days, then
180 mg QD, continuously, with or without food. Patients will take the
prescribed dose with water (recommended 240 mL).
Arm B (crizotinib):
Crizotinib will be administered as 250 mg orally BID, with or without food.
Patients will take the prescribed dose with water (recommended 240 mL).
Dose Modifications
Dose interruptions or reductions should be implemented for patients who
experience treatment-related AEs, based on the clinical judgment of the
investigator. Criteria for dose modifications of brigatinib for drug-related
toxicity are described in the protocol.
The European Medicines Agency (EMA) Summary of Product Characteristics (SmPC)
for crizotinib (XALKORI® SmPC, Pfizer, Inc.) will be used as a guideline for
dose modification of patients in the crizotinib arm and is detailed in the
protocol
Intervention
Not applicable
Study burden and risks
See protocolsection 11, page 38 till 51
Landsdowne Street 40
Cambridge MA 02139
US
Landsdowne Street 40
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Have histologically or cytologically confirmed stage IIIB (locally advanced
or recurrent and not a
candidate for definitive multimodality therapy) or stage IV NSCLC.
2. Patient must meet one of the following two criteria:
a. Have documentation of ALK rearrangement by a positive result from the Vysis®
ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the
Ventana ALK (D5F3) CDx Assay. The test must have been performed according to
the product*s instructions for use (IFU).
b. Have documented ALK rearrangement by a different test and adequate tissue
available for central laboratory testing by an FDA-approved test. Confirmation
of central test positivity is not required prior to randomization.
3. Have sufficient tumor tissue available for central analysis
4. Have at least 1 measurable (i.e., target) lesion per RECIST v1.1
5. Recovered from toxicities related to prior anticancer therapy to NCI CTCAE
v 4.0 grade *1. Note: treatment-related alopecia or peripheral neuropathy that
are grade >1 are allowed if deemed irreversible
6. Are a male or female patient *18 years old.
7. Have adequate organ function, as defined by the study protocol
8. Have Eastern Cooperative Oncology Group (ECOG) performance status *2
9. Have normal QT interval on screening ECG evaluation, defined as QT
interval corrected (Fridericia) (QTcF) of *450 milliseconds (msec) in males
or *470 msec in females.
10. For female patients of childbearing potential, have a negative pregnancy
test
documented prior to randomization.
11. For female and male patients who are fertile, agree to use a highly
effective
form of contraception with their sexual partner during the dosing period and
for a period of at least 4 months after the end of treatment with brigatinib
and at least 3 months after the end of treatment with crizotinib, as defined by
the study protocol
12. Provide signed and dated informed consent indicating that the patient has
been informed of all pertinent aspects of the study, including the potential
risks, and is willingly participating.
13. Have the willingness and ability to comply with scheduled visit and study
procedures.
Exclusion criteria
1. Previously received an investigational antineoplastic agent for NSCLC.
2. Previously received any prior TKI, including ALK-targeted TKIs.
3. Previously received more than 1 regimen of systemic anticancer therapy for
locally advanced or metastatic disease.
4. Received chemotherapy or radiation within 14 days of first dose of study
drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation
therapy (SBRT).
5. Received anti-neoplastic monoclonal antibodies within 30 days of the first
dose of study drug.
6. Had major surgery within 30 days of the first dose of study drug, minor
surgical procedures such as catheter placement or minimally invasive biopsies
are allowed.
7. Have been diagnosed with another primary malignancy other than NSCLC, except
for adequately treated non-melanoma skin cancer or cervical cancer in situ;
definitively treated non-metastatic prostate cancer; or patients with another
primary malignancy who are definitively relapse-free with at least 3 years
elapsed since the diagnosis of the other primary malignancy.
8. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening
or asymptomatic disease requiring an increasing dose of corticosteroids to
control symptoms within 7 days prior to randomization.
9. Have current spinal cord compression (symptomatic or asymptomatic and
detected by radiographic imaging). Patients with leptomeningeal disease and
without cord compression are allowed.
10. Be pregnant, planning a pregnancy, or breastfeeding
11. Have significant, uncontrolled, or active cardiovascular disease as defined
by the study protocol
12. Have uncontrolled hypertension.
13. Have a history or the presence at baseline of pulmonary interstitial
disease, drug-related pneumonitis, or radiation pneumonitis.
14. Have an ongoing or active infection
15. Have a known history of human immunodeficiency virus (HIV) infection.
16. Have a known or suspected hypersensitivity to brigatinib or its excipients
and/or crizotinib or its excipients.
17. Have malabsorption syndrome or other gastrointestinal (GI) illness or
condition
18. Have any condition or illness that, in the opinion of the investigator,
would
compromise patient safety or interfere with the evaluation of the study drug.
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 | EUCTR2015-003447-19-NL |
| ClinicalTrials.gov | NCT02737501 |
| CCMO | NL57216.042.16 |