Lorlatinib in ALK Inhibitor Treated Unresectable Advanced/Recurrent ALK-Positive Non Small Cell Lung Cancer Patients in India

SINGLE-ARM STUDY TO EVALUATE THE SAFETY OF LORLATINIB IN ALK INHIBITOR-TREATED UNRESECTABLE ADVANCED AND/OR RECURRENT ALK-POSITIVE NON-SMALL CELL LUNG CANCER PARTICIPANTS IN INDIA

Lorlatinib is a third-generation, oral, reversible, ATP-competitive, macrocyclic TKI of ALK and ROS1. Lorlatinib was specifically designed to penetrate the CNS and to overcome known secondary resistance mutations in the ALK tyrosine kinase domain.

This is a Phase 4, open-label, multicenter, non-randomized, prospective, single arm study to evaluate the safety and tolerability of lorlatinib in adult participants with unresectable advanced and/or recurrent ALK-positive NSCLC with resistance or intolerance to at least 1 prior ALK inhibitor treatment.

This study is being conducted as a post approval study to fulfill Central Drugs Standard Control Organization (CDSCO) request relating to additional information on use of Lorlatinib in Indian patients.

Inclusion Criteria:

1. Evidence of histologically or cytologically confirmed diagnosis of unresectable advanced and/or recurrent NSCLC that carries an ALK rearrangement, as detected by an appropriate test.

2. Disease progression or intolerance to 1 previous treatment with ALK TKI. Participants may have also had prior chemotherapy for their advanced and/or recurrent disease.

3. Participants with asymptomatic CNS metastases (including participants controlled with stable or decreasing steroid use within the last 2 weeks prior to study enrollment) will be eligible.

4. Age ≥18 years.

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2.

6. Adequate hematologic and renal function as defined as:

   1. Absolute neutrophil count (ANC) ≥1,000/mm3;
   2. Platelets ≥50,000/mm3;
   3. Hemoglobin ≥8 g/dL;
   4. Estimated creatinine clearance ≥30 mL/min as calculated using the method standard for the institution.

7. Adequate liver function, including:

   1. Total serum bilirubin ≤1.5 × upper limit of normal (ULN);
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤5.0 × ULN in case of liver metastases).

8. Adequate pancreatic function, including:

   1. Serum total amylase ≤1.5 × ULN.*
   2. Serum lipase <1.5 × ULN. *if total amylase >1.5 × ULN, but pancreatic amylase is within the ULN, the participant may be enrolled.

9. Acute effects of any prior therapy 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. Systemic anticancer therapy completed within a minimum of 5 half-lives of study enrollment (unless clinically meaningful tumor flare per discretion of the Investigator, in which discussion with the Sponsor is warranted).

11. Evidence of a personally signed and dated informed consent document indicating that the participant (or a legally acceptable representative) has been informed of all pertinent aspects of the study.

12. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

13. Pregnancy test for females of childbearing potential negative at Screening or female participants who are not of childbearing potential. Male and female participants of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception from the time of Screening, throughout the study and for 3 months after the last dose of assigned treatment, 6 months if female participants.

Exclusion Criteria:

1. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study enrollment. Palliative radiation (<10 fractions) must have been completed at least 48 hours prior to study enrollment. Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study enrollment. Whole brain radiation must have completed at least 4 weeks prior to study enrollment. Prior irradiation to >25% of the bone marrow.

2. 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.

3. Known prior or suspected severe hypersensitivity to study drug or any component in its formulation.

4. Active and clinically significant bacterial, fungal, or viral infection.

5. 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 atrioventricular (AV) block (unless paced) or any AV block with PR interval >220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 beats per minute (bpm) (unless participant is otherwise healthy such as long distance runners, etc.), machine read ECG with QT interval corrected for heart rate (QTc) >470 msec, or congenital long QT syndrome.

6. History or known presence of interstitial fibrosis, interstitial lung disease (ILD), pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis.

7. 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 participant inappropriate for enrollment in this study.

8. Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ [DCIS] of the breast or localized and presumed cured prostate cancer) within the last 3 years prior to enrollment.

9. 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 categories described below) within 12 days prior to the first dose of lorlatinib:

   1. Known strong cytochrome (CYP)3A inducers (eg, carbamazepine, enzalutamide, mitotane, rifampin, St. John's Wort).
   2. Known strong CYP3A inhibitors (eg, grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], boceprevir, cobicistat, clarithromycin, conivaptan, diltiazem, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nelfinavir, paritaprevir, posaconazole, ritonavir alone and with elvitegravir or indinavir or lopinavir or paritaprevir or ombitasvir or dasabuvir or saquinavir or tipranavir, telaprevir and voriconazole). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
   3. Known CYP3A substrates with narrow therapeutic index, such as pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil, fentanyl (including transdermal patch) or ergot alkaloids (ergotamine, dihydroergotamine).
   4. Known permeability glycoprotein (P-gp) substrates with a narrow therapeutic index (eg, digoxin).

10. Participants 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 participants who are Pfizer employees directly involved in the conduct of the study.

11. Participation in other studies involving investigational drug(s) (Phases 1-4) during study participation.

12. Breastfeeding female participants.