This study has been transitioned to CTIS with ID 2024-513454-29-00 check the CTIS register for the current data. Primary:To evaluate the efficacy and safety of Ensartinib vs. crizotinib in patients with ALK-positive NSCLC that have received up to 1…
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Brief title
Condition
- Other condition
Synonym
Health condition
longkanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression-free survival (PFS) as assessed by independent radiology review
based on RECIST v. 1.1 criteria.
Secondary outcome
• Key Secondary Efficacy Endpoints: Overall survival, CNS response rate (based
on IRR), time to CNS progression (based on IRR), objective response rate (based
on IRR)
• Other Secondary Efficacy Endpoints: PFS (based on investigator assessment),
ORR (based on investigator assessment), time to response (based on investigator
assessment and IRR), duration of response (based on investigator assessment and
IRR), CNS response rate (based on investigator assessment ), time to CNS
progression (based on investigator assessment)..
Exploratory:
Patient reported time to deterioration (TTD) as measured by the EORTC C30/LC13
QoL questionnaire and Lung Cancer Symptom Scale (LCSS), patient reported
healthrelated quality of life (HRQoL) as measured by the EORTC C30/LC13 QoL
questionnaire and LCSS, pharmacodynamic (PD) and possible pharmacogenetic (PG)
assessments.
Background summary
The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is
aberrant in a variety of malignancies. ALK was originally discovered in
anaplastic large cell lymphoma (ALCL) as part of a chromosomal translocation
t(2,5), which fuses the C-terminal kinase domain of ALK
encoded on chromosome 2p23 to the N-terminus of nucleophosmin (NPM) on
chromosome 5q35 (Morris et al. 1994). Subsequently, a variety of ALK fusion
proteins have been found in multiple malignancies, including inflammatory
myofibroblastic tumor (IMT) (Lawrence et al. 2000) and non-small cell lung
cancer (NSCLC) (Soda et al. 2007; Choi et al. 2008; Koivunen et al. 2008;
Takeuchi et al. 2008; Takeuchi et al. 2009; Wong et al. 2009; Horn and Pao
2009; Rikova et al. 2007). All ALK fusions tested biologically to date have
demonstrated gain of
function properties (Morris et al. 1994; Soda et al. 2007; Koivunen et al.
2008; Takeuchi et al. 2009). Activating mutations in wild-type ALK have also
been identified in both familial and sporadic neuroblastoma. Most of these
activating mutations occur within the tyrosine kinase
domain and are transforming in vitro and in vivo (Mosse et al. 2008; George et
al 2008; Janoueix-Leorosey et al. 2008; Chen et al 2008). Importantly, the
activity of cancer-specific ALK variants is required for tumor maintenance.
Thus, ALK mutants can serve as *Achilles
heels* to be exploited therapeutically. Multiple preclinical studies have shown
that specific small molecule ALK tyrosine kinase inhibitors (TKIs) can delay
tumor growth and/or induce tumor regression in xenograft and transgenic models
(Soda et al. 2007; Choi et al. 2008; Koivunen et
al. 2008; Sabbatini et al. 2009). Based on such promising nonclinical studies,
ALK TKIs entered into clinical trials. The first
agent in humans was crizotinib (Xalkori®, Pfizer, also known as PF-2341066 or
PF-1066), an orally available small molecule ATP-mimetic compound that was
approved for commercial use in the U.S. in August 2011 for the treatment of
metastatic NSCLC that is ALK-positive.
Crizotinib was originally designed as a MET inhibitor but was recognized to
have *off-target* anti-ALK activity (Zou et al. 2007). Strikingly, in a Phase 1
study, patients with ALK fusionpositive NSCLC demonstrated a >60% radiographic
response rate (Bang et al. 2008). Crizotinib
has been shown to be superior to chemotherapy in the first and second line
treatment of patients with ALK fusion-positive NSCLC. By contrast, chemotherapy
response rates are <10% in previously treated patients with unselected NSCLC
(Hanna et al. 2004). Several other ALK
TKIs have entered into clinical trials, with ceritinib (Zykadia*, Novartis,
also known as LDK378) being approved in the U.S. in 2014 for use in patients
that have progressed on or are intolerant to crizotinib.
Xcovery Holding Company, LLC (the Sponsor) has developed X-396, a novel potent
and specific ALK inhibitor with potential therapeutic relevance. In in vitro
and in vivo nonclinical studies, X-396 exhibited a favorable effectiveness
profile, including anti-tumor activity against multiple ALK variants including
some that are resistant or become resistant to crizotinib.
Study objective
This study has been transitioned to CTIS with ID 2024-513454-29-00 check the CTIS register for the current data.
Primary:
To evaluate the efficacy and safety of Ensartinib vs. crizotinib in patients
with ALK-positive NSCLC that have received up to 1 prior chemotherapy regimen
and no prior ALK tyrosine kinase inhibitor (TKI).
Secondary:
To obtain additional pharmacokinetic (PK) data on Ensartinib from sparse PK
sampling from patients at selected sites.
To compare the quality of life (QoL) in patients receiving Ensartinib vs.
crizotinib
Exploratory:
To evaluate the status of exploratory biomarkers and correlate with clinical
outcome.
To obtain germline DNA samples for possible pharmacogenetic analysis in the
event that outliers with respect to efficacy, tolerability/safety, or exposure
are identified.
Study design
A Phase 3 open-label, randomized study of the ALK inhibitors Ensartinib and
crizotinib given as single agents.Patients will be randomized 1:1.
Intervention
Not applicable.
Study burden and risks
See Protocol Section 9, page 31 up to and including 35 (and Appendix E).
Patient diary must be completed.
168 SE 1st Street, 11th floor 168 SE 1st Street, 11th floor
Miami, FL 33131
US
168 SE 1st Street, 11th floor 168 SE 1st Street, 11th floor
Miami, FL 33131
US
Listed location countries
Age
Inclusion criteria
1.Histologically or cytologically confirmed diagnosis of advanced or
recurrent (Stage IIIB not amenable for multimodality treatment) or
metastatic (Stage IV) NSCLC that is ALK-positive by an FDA-approved assay
performed centrally. Patients must be ALK positive by local test prior to
submitting tissue to the central lab. Randomization will occur after ALK
positive confirmation is received from the central lab. Patients may have
received up to 1 prior chemotherapy regimen for mestatic disease , which may
also include maintenance therapy.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0
to 2.
3. Life expectancy of at least 12 weeks.
4. Ability to swallow and retain oral medication.
5. Adequate organ system function, defined as follows:
a. Absolute neutrophil count (ANC) >=1.5 x 109/L
b. Platelets >=100 x 109/L
c. Hemoglobin >=9 g/dL (>=90 g/L) Note that transfusions are allowed to
meet the required hemoglobin level.
d. Total bilirubin <=1.5 times the upper limit of normal (ULN)
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 x
ULN if no liver involvement or <=5 x ULN with liver involvement.
f. Creatinine <=1.5 x ULN. If >1.5 x ULN, patient may still be eligible if
calculated creatinine clearance >=50 mL/min (0.83 mL/s) as calculated by the
Cockcroft-Gault method.
6. Brain metastases allowed if asymptomatic at study baseline. Patients with
untreated brain metastases must not be on corticosteroids. If patients have
neurological symptoms or signs due to CNS metastases, patients need to complete
whole brain radiation or focal treatment at least 14 days
before start of study treatment and be asymptomatic on stable or decreasing
doses of corticosteroids at baseline.
7.Men with partners of childbearing potential willing to use adequate
contraceptive measures during the study and for 90 days after the last dose of
study medication.
8.Women who are not of child-bearing potential, and women of childbearing
potential who agree to use adequate contraceptive measures during the study and
for 90 days after the last dose of study medication, and who have a negative
serum or urine pregnancy test within 1 week prior to initial trial treatment.
9. Patients must be >=18 years of age.
10. Patients must have measurable disease per RECIST v. 1.1.
11. Patients must be ALK-positive by IHC. Testing will be done centrally;
however, patients will be allowed to enroll based on local results (positive by
FISH or IHC), if available.
12. Willingness and ability to comply with the trial and follow-up procedures.
13. Ability to understand the nature of this trial and give written informed
consent.
Exclusion criteria
1. Patients that have previously received an ALK TKI or PD-1 or PD-L1 therapy,
and patients currently receiving cancer therapy (i.e., other targeted
therapies, chemotherapy, radiation therapy, immunotherapy, biologic therapy,
hormonal therapy, surgery and/or tumor embolization).
2. Use of an investigational drug within 21 days prior to the first dose of
study drug. Note that to be eligible, any drug-related toxicity should have
recovered to Grade 1 or less, with the exception of alopecia.
3. Any chemotherapy within 4 weeks, or major surgery or radiotherapy within the
last 14 days.
4. Patients with primary CNS tumors and leptomeningeal disease are ineligible.
5. Patients with a previous malignancy within the past 3 years (other than
curatively treated basal cell carcinoma of the skin, in situ carcinoma of the
cervix, or any cancer that is considered to be cured and have no impact on PFS
and OS for the current NSCLC).
6. Concomitant systematic use of anti-cancer herbal medications. These should
be stopped prior to study entry.
7.Patients receiving
a. strong CYP3A inhibitors (including, but not limited to, atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin,
voriconazole, grapefruit, grapefruit juice)
b. strong CYP3A inducers (including, but not limited to, carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort)
c. CYP3A substrates with narrow therapeutic window (including, but not
limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine,
fentanyl, pimozide, quinidine, sirolimus, tacrolimus).
8. Women who are pregnant or breastfeeding.
9. Presence of active gastrointestinal (GI) disease or other condition that
will interfere significantly with the absorption, distribution, metabolism, or
excretion of study medications.
10. Patients at risk for GI perforation
11. Clinically significant cardiovascular disease including:
a. QTcF interval >450 ms for men and >470 ms for woman, symptomatic bradycardia
<45 beats per minute or other significant ECG abnormalities in the
investigator's opinion.
b. Clinically uncontrolled hypertension in the investigator's opinion (e.g.,
blood pressure >160/100 mmHg; note that isolated elevated readings considered
to not be indicative of uncontrolled hypertension are allowed).
The following within 6 months prior to Cycle 1 Day 1:
a. Congestive heart failure (New York Heart Class III or IV).
b. Arrhythmia or conduction abnormality requiring medication. Note: patients
with atrial fibrillation/flutter controlled by medication and arrhythmias
controlled by pacemakers are eligible.
c. Severe/unstable angina, coronary artery/peripheral bypass graft, or
myocardial infarction.
d. Cerebrovascular accident or transient ischemia.
12. Patients who are immunosuppressed (including known HIV infection), have a
serious active infection at the time of treatment, have interstitial lung
disease/pneumonitis, or have any serious underlying medical condition that
would impair the ability of the patient to receive protocol treatment. Patients
with controlled hepatitis C, in the investigator's opinion, are allowed.
Patients with known hepatitis B must be HBeAg and HB viral DNA negative for
enrollment. Note that, because of the high prevalence, all patients in the
Asia-Pacific region (except Australia, New Zealand, and Japan) must be tested
and, if HBsAg positive, must be HBeAg and HB viral DNA negative for enrollment.
13. Known hypersensitivity to tartrazine, a dye used in ensartinib 100 mg
capsule.
14. Psychological, familial, sociological, or geographical conditions that do
not permit compliance with the protocol.
15. Concurrent condition that in the investigator's opinion would jeopardize
compliance with the protocol or would impart excessive risk associated with
study participation that would make it inappropriate for the patient to be
enrolled.
16. Inability or unwillingness to comply with study and/or follow-up procedures
outlined 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 |
|---|---|
| EU-CTR | CTIS2024-513454-29-00 |
| EudraCT | EUCTR2015-004147-40-NL |
| CCMO | NL58390.068.16 |