Trial Title:
Lorlatinib as the First-line Treatment in China Advanced ALK+ NSCLC
NCT ID:
NCT06092086
Condition:
ALK Positive Non-small Cell Lung Cancer
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Single drug administration
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Loratinib
Description:
Continuous daily PO dosing of lorlatinib 100mg QD.
Arm group label:
CROWN Criteria (CC) Cohort、Compassionate use (CU) Cohort
Other name:
LORBRENA
Summary:
This phase II study is aim to investigate the efficacy, resistance mechanism, safety
profile of first-line lorlatinib in China advanced ALK+ non-small cell lung cancer
(NSCLC). Participants will receive continuous daily PO dosing of lorlatinib 100mg QD.
Detailed description:
This is a patient-centric, two cohorts, open-label, multi-center, phase II study in
China, designed to prospectively enroll 126 advanced ALK+NSCLC patients, including 84
subjects fulfilled CROWN criteria as "CROWN criteria (CC) cohort", and another 42
subjects beyond CROWN criteria as "compassionate use (CU) cohort". Subjects will receive
continuous daily PO dosing of lorlatinib 100mg QD, from the date of first dosing until
disease progression, unacceptable toxicity, or withdrawal for any reason, or death,
whichever occurs first. The primary endpoints are progression-free survival (PFS) of CC
cohort per investigator, and resistance mechanism of first-line lorlatinib. Secondary
endpoints are 1/2/3-year PFS, cumulative rate of central nervous system (CNS)
progression, intracranial-time to progression (IC-TTP), objective response rate (ORR) and
intracranial ORR (IC-ORR), overall survival (OS), safety and PRO. Exploratory endpoints
include evaluation of candidate biomarkers of sensitivity or resistance to lorlatinib,
dynamic ctDNA change during treatment, and effective treatment after lorlatinib
resistance.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Inclusion Criteria of CROWN Criteria (CC) Cohort
Subjects must meet all of the following inclusion criteria to be eligible for enrollment
into the study:
1. Diagnosis:
1. Study Population: Patients with histologically or cytologically confirmed
diagnosis of locally advanced [(Stage IIIB/C not amenable for multimodality
treatment) or metastatic (Stage IV) by American Joint Committee on Cancer
(AJCC) v 7.0] ALK-positive NSCLC where ALK status is determined by the Ventana
ALK (D5F3) Companion Diagnostic (CDx) IHC test performed on the Ventana ULTRA
or XT Platforms, FISH, PCR, or next generation sequencing (NGS), or circulating
tumor DNA (ctDNA).
2. Tumor Requirements: At least 1 extracranial measurable target lesion per RECIST
v. 1.1 that has not been previously irradiated. CNS metastases are allowed if
asymptomatic and:
1. Either untreated and not currently requiring corticosteroid treatment, or
on a stable or decreasing dose of ≤10 mg QD prednisone or equivalent; or
2. Local treatment has been completed with full recovery from the acute
effects of radiation therapy or surgery prior to randomization, and if
corticosteroid treatment for these metastases has been withdrawn for at
least 4 weeks with neurological stability; or
3. In case of leptomeningeal disease (LMD) or carcinomatous meningitis (CM)
if visualized on magnetic resonance imaging (MRI), or if baseline CSF
positive cytology is available.
3. Tissue Requirements: All patients must have an archival formalin fixed,
paraffin embedded (FFPE) tissue specimen available and collected prior to
randomization. If archived tissue is unavailable, then a mandatory de novo
biopsy must be performed.
2. No prior systemic NSCLC treatment for advanced (Stage IIIB/C not amenable for
multimodality treatment) or metastatic (Stage IV) disease, including molecularly
targeted agents (e.g., ALK TKIs), angiogenesis inhibitors, immunotherapy, or
chemotherapy. Prior treatment for earlier Stages of the NSCLC only allowed if
completed more than 12 months prior to randomization.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2.
4. Age ≥18 years.
5. Adequate Bone Marrow Function, including:
1. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥1.5 x 109/L;
2. Platelets ≥100,000/mm3 or ≥100 x 109/L;
3. Hemoglobin ≥9 g/dL.
6. Adequate Pancreatic Function, including:
1. Serum total amylase ≤1.5 x upper limit of normal (ULN)*;
2. Serum lipase ≤1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase
is within the ULN, then patient may be enrolled.
7. Adequate Renal Function, including:
a. Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as
calculated using the method standard for the institution.
8. Adequate Liver Function, including:
1. Total serum bilirubin ≤1.5 x ULN;
2. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN
(≤5.0 x ULN in case of liver metastases).
9. Acute effects of prior radiotherapy resolved to baseline severity or to CTCAE Grade
≤1 except for AEs that in the investigator's judgment do not constitute a safety
risk for the patient.
10. Serum pregnancy test (for females of childbearing potential) negative at screening.
Female patients of non-childbearing potential must meet at least 1 of the following
criteria:
1. Achieved postmenopausal status, defined as follows: cessation of regular menses
for at least 12 consecutive months with no alternative pathological or
physiological cause (which may be confirmed with a serum follicle-stimulating
hormone [FSH] level confirming the postmenopausal state if appropriate);
2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
3. Have medically confirmed ovarian failure. All other female patients (including
female patients with tubal ligations) are considered to be of childbearing
potential.
11. Evidence of a personally signed and dated informed consent document indicating that
the patient (or a legally acceptable representative) has been informed of all
pertinent aspects of the study.
12. Willing and able to comply with scheduled visits, treatment plans, laboratory tests
and other procedures.
Inclusion Criteria of Compassionate use (CU) Cohort
1. Diagnosed as ALK-positive NSCLC as in CC cohort, but not fulfilled CC cohort
inclusion criteria 2~9 as above mentioned.
2. No prior ALK TKI treatment for advanced (Stage IIIB/C not amenable for multimodality
treatment) or metastatic (Stage IV) disease (e.g., alectinib, brigatinib).
3. Serum pregnancy test (for females of childbearing potential) negative at screening.
4. Evidence of a personally signed and dated informed consent document indicating that
the patient (or a legally acceptable representative) has been informed of all
pertinent aspects of the study.
5. Willing and able to comply with scheduled visits, treatment plans, laboratory tests
and other procedures.
Exclusion Criteria:
Subjects presenting with any of the following characteristics/conditions will not be
included in this clinical study:
1. Spinal cord compression unless the patient has good pain control attained through
therapy, and there is stabilization or recovery of neurological function for the 4
weeks prior to randomization.
2. Major surgery within 4 weeks prior to randomization. Minor surgical procedures
(e.g., port insertion) are not excluded, but sufficient time should have passed for
adequate wound healing.
3. Radiation therapy within 2 weeks prior to randomization, including stereotactic or
partial brain irradiation. Patients who complete whole brain irradiation within 4
weeks prior to randomization or palliative radiation therapy outside of the CNS
within 48 hours prior to randomization will also not be included in the study.
4. Gastrointestinal abnormalities, including inability to take oral medication;
requirement for intravenous alimentation; prior surgical procedures affecting
absorption including total gastric resection or lap band; active inflammatory
gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease;
treatment for active peptic ulcer disease in the past 6 months; malabsorption
syndromes.
5. Known prior or suspected severe hypersensitivity to study drugs or any component in
their formulations.
6. Active and clinically significant bacterial, fungal, or viral infection including
hepatitis B virus (HBV) or hepatitis C virus (HCV) (e.g., in case of known HBsAg or
HCV antibody positivity), known human immunodeficiency virus (HIV), or acquired
immunodeficiency syndrome (AIDS)-related illness.
7. Clinically significant vascular (both arterial and venous) and non-vascular cardiac
conditions, (active or within 3 months prior to enrollment), which may include, but
are not limited to:
1. Arterial disease such as cerebral vascular accident/stroke (including Transient
Ischemic Attack -TIA), myocardial infarction, unstable angina;
2. Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary
embolism;
3. Non-vascular cardiac disease such as congestive heart failure (New York Heart
Association Classification Class ≥ II), second-degree or third-degree AV block
(unless paced) or any AV block with PR >220 msec; or ongoing cardiac
dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any
grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such
as long-distance runners, etc.), machine-read Electrocardiogram (ECG) with QTc
>470 msec, or congenital long QT syndrome.
8. Patients with predisposing characteristics for acute pancreatitis according to
investigator judgment (e.g., uncontrolled hyperglycemia, current gallstone disease)
in the last month prior to randomization.
9. History of extensive, disseminated, bilateral or presence of Grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung
disease, obliterative bronchiolitis, and pulmonary fibrosis.
10. Evidence of active malignancy (other than NSCLC, non-melanoma skin cancer, or
localized prostate cancer or any in situ cancer which does not currently require
treatment) within the last 3 years prior to randomization.
11. Concurrent use of any of the following food or drugs (consult the sponsor if in
doubt whether a food or a drug falls into any of the above categories) within 12
days prior to the first dose of lorlatinib.
1. Known strong CYP3A inhibitors (e.g., strong CYP3A inhibitors: grapefruit juice
or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos],
boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole,
ritonavir alone and with danoprevir or elvitegravir or indinavir or lopinavir
or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir,
telaprevir, troleandomycin, and voriconazole. The topical use of these
medications (if applicable), such as 2% ketoconazole cream, is allowed.
2. Known CYP3A substrates with narrow therapeutic index, such as astemizole*,
terfenadine*, cisapride*, pimozide, quinidine, tacrolimus, cyclosporine,
sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot
alkaloids (ergotamine, dihydroergotamine) (*withdrawn from US market).
3. Known strong CYP3A inducers (e.g., carbamazepine, enzalutamide, mitotane,
phenytoin, rifampin, St. John's Wort). d. Known P-gp substrates with a narrow
therapeutic index (e.g., digoxin).
12. Other severe acute or chronic medical or psychiatric condition, including recent
(within the past year) or active suicidal ideation or behavior, or laboratory
abnormality that may increase the risk associated with study participation or
investigational product 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.
13. Patients who are investigational site staff members directly involved in the conduct
of the study and their family members, site staff members otherwise supervised by
the Investigator, or patients who are Pfizer employees, including their family
members, directly involved in the conduct of the study.
14. Participation in other studies involving investigational drug(s) within 2 weeks
prior to study entry and/or during study participation.
15. Pregnant female patients; breastfeeding female patients; fertile male patients and
female patients of childbearing potential who are unwilling or unable to use a
highly effective method of contraception as outlined in this protocol for the
duration of the study and for at least 97 days, if male or 35 days if female, after
the last dose of investigational product under lorlatinib.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Guangdong Provincial Perople's Hospital
Address:
City:
Guangzhou
Zip:
023187
Country:
China
Status:
Recruiting
Contact:
Last name:
Jiaxin Lin, PhD
Phone:
+8618928737479
Email:
linjiaxin@gdph.org.cn
Investigator:
Last name:
Yi-Long Wu, MD
Email:
Principal Investigator
Start date:
August 18, 2023
Completion date:
August 1, 2030
Lead sponsor:
Agency:
Guangdong Association of Clinical Trials
Agency class:
Other
Source:
Guangdong Association of Clinical Trials
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06092086
