A Phase 3, randomized, open label study of lorlatinib (PF 06463922) monotherapy versus crizotinib monotherapy in the first line treatment of patients with advanced ALK positive non small cell lung cancer

see section 4.1 in protocol:
1.Diagnosis:
a.Study Population: Patients with histologically or cytologically confirmed
diagnosis of locally advanced [(Stage IIIB 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
FDA-approved (for use in US), CE (Conformité Européene) marked (for EU and
other countries that accept CE marking), and PMDA(Pharmaceuticals and Medical
Devices Agency)- approved (for use in Japan) Ventana ALK (D5F3) Companion
Diagnostic (CDx) IHC test performed on the Ventana ULTRA or XT platforms (refer
to Section 6.1.1.1 for any prescreening activity related to ALK determination);
b. 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:
i.Asymptomatic: either not currently requiring corticosteroid treatment, or on
a stable or decreasing dose of <= 10 mg QD prednisone or equivalent; or
ii. Previously diagnosed and 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and if corticosteroid treatment for these metastases has been withdrawn for at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
iii. Leptomeningeal disease (LMD) or carcinomatous meningitis (CM) if
visualized on MRI (magnetic resonance imaging), or if baseline CSF positive
cytology is available.
c. Tissue Requirements: All participants 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,, including molecularly targeted agents,
angiogenesis inhibitors, immunotherapy, or chemotherapy. Adjuvant/neoadjuvant
NSCLC treatment 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 (or >=20 years as required by local regulation).
5. Adequate Bone Marrow Function, including:
a. Absolute Neutrophil Count (ANC) >= 1,500/mm3 or >= 1.5 x 109/L;
b. Platelets >=100,000/mm3 or >=100 x 109/L;
c. Hemoglobin >= 9 g/dL.
6. Adequate Pancreatic Function, including:
a. Serum total amylase <= 1.5 x upper limit of normal (ULN)*;
b. 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:
a. Total serum bilirubin <= 1.5 x ULN;
b. 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 participant.
10. Serum pregnancy test (for females of childbearing potential) negative at
screening. Female participants of non-childbearing potential must meet at least
1 of the following criteria:
• Achieved postmenopausal status, defined as follows: cessation of regular
menses for at least 12 consecutive months with no alternative pathological or
physiological cause; status may be confirmed with a serum follicle-stimulating
hormone (FSH) level confirming the postmenopausal state;
• Have undergone a documented hysterectomy and/or bilateral oophorectomy;
• Have medically confirmed ovarian failure.
All other female participants (including female participants 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.

See protocol section 4.2:
Patients with any of the following characteristics/conditions will not be
included in the study:
1. Spinal cord compression unless the participant 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 (eg, 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 nonvascular
cardiac conditions, (active or within 3 months prior to enrollment), which may
include, but are not limited to:
- Arterial disease such as cerebral vascular accident/stroke (including
Transient Ischemic Attack -TIA), myocardial infarction, unstable angina;
- Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary
embolism;
-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 participant 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 (eg, 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,
in situ cervical cancer, papillary thyroid cancer, lobular carcinoma in
situ/ductal carcinoma in situ (LCIS/DCIS) of the breast, or localized prostate
cancer) 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 or crizotinib.
a. known strong CYP3A inhibitors (eg, 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.
b. 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).
c. known strong CYP3A inducers (eg, avasimibe, carbamazepine, phenobarbital,
phenytoin, rifatutin, rifampin, St. John*s Wort).
d. known P gp substrates with a narrow therapeutic index (eg, 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 methods 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 if under
lorlatinib or 90 days if under crizotinib.