LORLATINIB for Advanced ALK-positive non-small cell lung cancer

Inclusion criteria

• {"criterion_text":"- 1.\tDiagnosis: a.\tStudy Population: Participants 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.\tTumor 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.\tEither untreated and not currently requiring corticosteroid treatment, or on a stable or decreasing dose of ≤10 mg QD prednisone or equivalent; or 2.\tLocal 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of radiation therapy or surgery prior to randomization, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability; or 3.\tIn case of leptomeningeal disease (LMD) or carcinomatous meningitis (CM) if visualized on magnetic resonance imaging (MRI), or if baseline CSF positive cytology is available. c.\tTissue 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."}
• {"criterion_text":"- 10.\tSerum 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: •\tAchieved 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); •\tHave undergone a documented hysterectomy and/or bilateral oophorectomy; •\tHave medically confirmed ovarian failure. All other female participants (including female participants with tubal ligations) are considered to be of childbearing potential."}
• {"criterion_text":"- 11.\tEvidence 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."}
• {"criterion_text":"- 12.\tWilling and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures."}
• {"criterion_text":"- 2.\tNo prior systemic NSCLC treatment for advanced (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) disease, including molecularly targeted agents (eg, 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."}
• {"criterion_text":"- 3.\tEastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1, or 2."}
• {"criterion_text":"- 4.\tAge ≥18 years (or ≥20 years as required by local regulation)."}
• {"criterion_text":"- 5.\tAdequate Bone Marrow Function, including: a.\tAbsolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥1.5 x 109/L; b.\tPlatelets ≥100,000/mm3 or ≥100 x 109/L; c.\tHemoglobin ≥9 g/dL."}
• {"criterion_text":"- 6.\tAdequate Pancreatic Function, including: a.\tSerum total amylase ≤1.5 x upper limit of normal (ULN)*; b.\tSerum lipase ≤1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then participant may be enrolled."}
• {"criterion_text":"- 7.\tAdequate Renal Function, including: a.\tSerum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 ML/min as calculated using the method standard for the institution."}
• {"criterion_text":"- 8.\tAdequate Liver Function, including: a.\tTotal serum bilirubin ≤1.5 x ULN; b.\tAspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN (≤5.0 x ULN in case of liver metastases)."}
• {"criterion_text":"- 9.\tAcute 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."}

Exclusion criteria

• {"criterion_text":"- 1.\tSpinal 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."}
• {"criterion_text":"- 10.\tEvidence 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."}
• {"criterion_text":"- 11.\tConcurrent 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 below categories) within 12 days prior to the first dose of lorlatinib or crizotinib. a.\tKnown 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.\tKnown 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.\tKnown strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s Wort). d.\tKnown P gp substrates with a narrow therapeutic index (eg, digoxin)."}
• {"criterion_text":"- 12.\tOther 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 entry into this study."}
• {"criterion_text":"- 13. 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, including their family members, directly involved in the conduct of the study."}
• {"criterion_text":"- 14.\tParticipation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation."}
• {"criterion_text":"- 15.\tPregnant 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 if under lorlatinib or 90 days if under crizotinib."}
• {"criterion_text":"- 2.\tMajor 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."}
• {"criterion_text":"- 3.\tRadiation therapy within 2 weeks prior to randomization, including stereotactic or partial brain irradiation. Participants 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."}
• {"criterion_text":"- 4.\tGastrointestinal 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."}
• {"criterion_text":"- 5.\tKnown prior or suspected severe hypersensitivity to study drugs or any component in their formulations."}
• {"criterion_text":"- 6.\tActive and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV) (eg, in case of known HBsAg or HCV antibody positivity), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness."}
• {"criterion_text":"- 7.\tClinically 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: •\tArterial disease such as cerebral vascular accident/stroke (including Transient Ischemic Attack TIA), myocardial infarction, unstable angina; •\tVenous diseases such as cerebral venous thrombosis, symptomatic pulmonary embolism; •\tNon 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."}
• {"criterion_text":"- 8. Participants with predisposing characteristics for acute pancreatitis according to investigator judgment (eg, uncontrolled hyperglycemia, current gallstone disease) in the last month prior to randomization."}
• {"criterion_text":"- 9.\tHistory 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."}

Primary endpoints

• {"endpoint_text":"- •\tPFS based on blinded independent central review (BICR) assessment (RECIST v.1.1).","definition_or_measurement_approach":"Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) using RECIST v1.1 criteria."}

Secondary endpoints

• {"endpoint_text":"- •\tEfficacy: OS, PFS based on Investigator’s assessment, OR based on BICR and on Investigator’s assessment; intracranial OR (IC OR), IC TTP, DR and IC-DR, TTR and IC-TTR all by BICR (RECIST v. 1.1) and PFS2; IC-OR, IC-TTP, IC-DR, IC-TTR and DR based on the investigator’s assessment.","definition_or_measurement_approach":"Overall Survival (OS), Investigator-assessed PFS, Objective Response (OR) by BICR and Investigator, intracranial OR, intracranial time to progression (IC TTP), duration of response (DR) and intracranial DR, time to response (TTR) and intracranial TTR assessed by BICR per RECIST v1.1; PFS2. Also investigator-assessed versions of intracranial endpoints."}
• {"endpoint_text":"- •\tSafety: AEs (as graded by NCI CTCAE v.4.03); laboratory abnormalities (as graded by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate) and body weight; electrocardiograms (ECGs); echocardiogram or MUGA scan; ophthalmologic data.","definition_or_measurement_approach":"Safety assessed via adverse events graded per NCI CTCAE v4.03, laboratory abnormalities graded per CTCAE v4.03, vital signs, body weight, ECGs, echocardiogram/MUGA, and ophthalmologic assessments."}
• {"endpoint_text":"- •\tPROs as assessed by EORTC QLC C30, EORTC QLQ LC13, EQ 5D 5L.","definition_or_measurement_approach":"Patient-reported outcomes measured using EORTC QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L instruments."}
• {"endpoint_text":"- •\tTumor tissue biomarkers including, but not limited to, ALK gene rearrangement and/or mutation as measured by next generation sequencing (NGS) and/or immunohistochemistry (IHC).","definition_or_measurement_approach":"Tumor tissue biomarker analyses (e.g., ALK rearrangement/mutation) measured by NGS and/or IHC."}
• {"endpoint_text":"- •\tPeripheral blood cfDNA (circulating free Deoxyribonucleic acid) biomarkers including, but not limited to, ALK gene rearrangement and/or ALK kinase domain mutations.","definition_or_measurement_approach":"Peripheral blood cfDNA biomarker assessments for ALK rearrangements and ALK kinase-domain mutations."}

Belgium

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

03-04-2026

Processing Time Days

674

Number Of Sites

1

Number Of Participants

1

Italy

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

03-04-2026

Processing Time Days

674

Number Of Sites

10

Number Of Participants

12

Netherlands

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

02-04-2026

Processing Time Days

673

Number Of Sites

1

Number Of Participants

1

Poland

Earliest CTIS Part Ii Submission Date

08-07-2024

Latest Decision Or Authorization Date

07-04-2026

Processing Time Days

638

Number Of Sites

4

Number Of Participants

4

France

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

02-04-2026

Processing Time Days

673

Number Of Sites

6

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

07-04-2026

Processing Time Days

678

Number Of Sites

5

Number Of Participants

5

Germany

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

08-04-2026

Processing Time Days

679

Number Of Sites

3

Number Of Participants

3

Czechia

Earliest CTIS Part Ii Submission Date

29-05-2024

Latest Decision Or Authorization Date

02-04-2026

Processing Time Days

673

Number Of Sites

1

Number Of Participants

1

Primary sponsor

Full Name

Pfizer Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Syneos Health Inc.

Responsibilities

Investigator’s payments, patients’ payments; other sponsorDuties codes listed (1,12,6)

Name

Labcorp Development (Asia) Pte Ltd

Responsibilities

Biospecimen Management, Central Laboratory

Name

Labcorp Central Laboratory Services SARL

Responsibilities

Biospecimen Management, Central Laboratory

Name

Labcorp Central Laboratory Services LP

Responsibilities

Biospecimen Management, Central laboratory

Third parties

• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"sponsorDuties codes: 1, 12, 15 (Investigator’s payments, patients’ payments), 6","organisation_type":"Pharmaceutical company"}
• {"country":"Singapore","full_name":"Labcorp Development (Asia) Pte Ltd","duties_or_roles":"Biospecimen Management, Central Laboratory (sponsorDuties code 15)","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Biospecimen Management, Central Laboratory (sponsorDuties code 15)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Biospecimen Management, Central laboratory (sponsorDuties code 15)","organisation_type":"Pharmaceutical company"}