A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Lorlatinib
Intervention description: ALK inhibitor-treated ALK-positive NSCL treatment
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 109.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ALK positive; ALK inhibitor-treated; NSCLC

Summary:

      A Phase 2, multi center, open label, dual cohort study to evaluate the efficacy and safety of
      lorlatinib (PF 06463922) monotherapy in ALK inhibitor treated locally advanced or metastatic
      ALK positive non small cell lung cancer patients in China
    

Eligibility criteria:

        Inclusion Criteria:

          1. Evidence of histologically or cytologically confirmed diagnosis of locally advanced or
             metastatic ALK positive NSCLC where ALK status has been previously established by the
             Ventana ALK (D5F3) CDx Assay (Roche Diagnostics), the Vysis ALK Break Apart FISH Probe
             Kit (Abbott Molecular), or the EML4 ALK Fusion Gene Detection Kit (AmoyDx).

          2. Subject should have:

               1. (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor;

               2. (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib,
                  with or without prior crizotinib.

          3. Prior treatment with an ALK inhibitor must have completed 5 half lives prior to study
             entry.

          4. All Subjects must have at least 1 measurable extracranial target lesion according to
             RECIST v1.1 that has not been previously irradiated. CNS metastases are allowed if:

               1. Asymptomatic: either not currently requiring corticosteroid treatment, or on a
                  stable or decreasing dose of 10 mg QD prednisone or equivalent; or

               2. Previously diagnosed and treatment has been completed with full recovery from the
                  acute effects of radiation therapy or surgery prior to enrollment, and if
                  corticosteroid treatment for these metastases has been withdrawn for at least 4
                  weeks with neurological stability.

          5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2.

          6. Age 18 years (or 20 years as required by local regulation).

          7. Adequate bone marrow functions:

               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.

          8. Adequate pancreatic function:

               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 subject may be enrolled.

          9. Adequate renal function:

             a. Serum creatinine 1.5 x ULN or estimated creatinine clearance 60 mL/min as
             calculated using the method standard for the institution.

         10. Adequate liver function:

               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).

         11. Acute effects of prior radiotherapy and chemotherapy resolved to baseline severity or
             to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
             (CTCAE) Grade 1 except for AEs that in the investigator's judgment do not constitute a
             safety risk for the subject.

         12. Serum or urine pregnancy test (for females of childbearing potential) negative at
             screening. Female subjects 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 subjects (including
                  female subjects with tubal ligations) are considered to be of childbearing
                  potential.

         13. Evidence of a personally signed and dated informed consent document indicating that
             the subject (or a legally acceptable representative) has been informed of all
             pertinent aspects of the study.

         14. Willing and able to comply with the study scheduled visits, treatment plans,
             laboratory tests, and other procedures.

        Exclusion Criteria:

        Subjects with any of the following characteristics/conditions will not be included in the
        study:

          1. More than 1 prior chemotherapy regimen prior to enrollment in advanced/metastatic
             setting.

             If disease recurred/relapsed within the adjuvant chemotherapy treatment or <=6 months
             after the completion of the adjuvant chemotherapy, then the adjuvant chemotherapy is
             considered as the first line systemic chemotherapy to the disease.

          2. Systemic anti cancer therapy completed within a minimum of 5 half lives of study
             enrollment.

          3. Prior therapy with an antibody or drug specifically targeting T cell co stimulation or
             immune checkpoint pathways, including, but not limited to, anti programmed cell death
             protein 1 (anti PD 1), anti programmed cell death protein ligand 1 (anti PD L1), anti
             PD L2, anti cluster of differentiation 137 (anti CD137), or anti cytotoxic T
             lymphocyte associated antigen 4 (anti CTLA 4) antibody.

          4. Known epidermal growth factor receptor (EGFR) activating mutations; known prior
             therapy with EGFR TKI(s) (the prior treatment with brigatinib is allowed as an ALK
             TKI).

          5. Major surgery within 4 weeks prior to enrollment. Minor surgical procedures (eg, port
             insertion) are not excluded, but sufficient time should have passed for adequate wound
             healing.

          6. Radiation therapy within 2 weeks prior to enrollment. Palliative radiation must have
             been completed at least 48 hours prior to enrollment. Stereotactic or partial brain
             irradiation must have completed at least 2 weeks prior to enrollment. Whole brain
             irradiation must have completed at least 4 weeks prior to enrollment.

          7. Spinal cord compression unless the subject has good pain control attained through
             therapy, and there is complete recovery of neurological function for the 4 weeks prior
             to enrollment.

          8. 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.

          9. Known prior or suspected severe hypersensitivity to lorlatinib or any component in the
             formulation; known prior therapy with lorlatinib.

         10. Active and clinically significant bacterial, fungal, or viral infection including
             hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus
             (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.

         11. Clinically significant cardiovascular disease (both arterial and venous) and non
             vascular cardiac conditions, (active or within 3 months prior to enrollment, which may
             include, but not are 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;

               -  Nonvascular cardiac disease such as congestive heart failure (New York Heart
                  Association Classification Class ≥ II), second degree or third degree
                  atrioventricular block (unless paced) or any AV block with PR interval >220 msec;
                  or

               -  Ongoing cardiac dysrhythmias of CTCAE Grade ≥2, uncontrolled atrial fibrillation
                  of any grade, bradycardia defined as <50 bpm (unless subject is otherwise healthy
                  such as long distance runners, etc.), machine read electrocardiogram (ECG) with
                  QTc >470 msec, or congenital long QT syndrome.

         12. Subject with predisposing characteristics for acute pancreatitis according to
             investigator judgment, including but not limited to uncontrolled hyperglycemia,
             current gallstone disease, in the last month prior to enrollment.

         13. 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.

         14. Evidence of active malignancy (other than NSCLC, non melanoma skin cancer, or
             localized and presumed cured prostate cancer or any in situ cancer which does not
             currently require treatment) within the last 3 years prior to enrollment.

         15. 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 administration of lorlatinib:

               1. 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;

               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 (eg, carbamazepine, enzalutamide, mitotane,
                  phenytoin, rifampin, St. John's Wort);

               4. Known P glycoprotein (P gp) substrates with a narrow therapeutic index (eg,
                  digoxin).

         16. 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 and/or the sponsor, would make
             the subject inappropriate for entry into this study.

         17. Subject 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 subjects who are Pfizer employees, including their family members,
             directly involved in the conduct of the study.

         18. Participation in other studies involving investigational drug(s) within 2 weeks prior
             to study entry and/or during study participation.

         19. Pregnant female participants; breastfeeding female participants; fertile male
             participants and female participants 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.