Lorlatinib Plus Local Consolidation Therapy In ALK Positive Advanced Non-Small Cell Lung Cancer
This is an open-label, multicenter, randomized phase 2 trial for patients with tyrosine kinase inhibitor-naïve ALKrearranged advanced NSCLC. Subjects are initially treated with lorlatinib for 12 weeks.
⁃ Subjects must meet all the following criteria to be included in this study:
• Histologically or cytologically confirmed diagnosis of stage IV NSCLC (or recurrent NSCLC not a candidate for definitive multimodality therapy)
• Documented ALK re-arrangement as detected by: (1) FISH, (2) IHC, (3) tissue NGS, or (4) cfDNA NGS
• Subjects can be enrolled as (a) TKI naïve or (b) after/during 12 weeks of first line lorlatinib treatment without disease progression or (c) ≤4 weeks of first line alectinib, brigatinib or ensartinib treatment without disease progression, those patients must be switched to lorlatinib.
• Candidate for local consolidation therapy in the opinion of the treating physician.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Males or females ≥ 18 years. Because no dosing or adverse event data are currently available on the use of lorlatinib in combination with other agents in patients \<18 years of age, children are excluded from this study.
• Adequate organ function laboratory values, defined as:
∙ Absolute neutrophil count (ANC) ≥ 1.0 x 109/L or at least 1000/mm3 .Platelet count at least 75,000/mm3 or at least 75 x 109/L
‣ Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline
‣ Serum creatinine ≤ 1.5 × ULN or ≥ 45mL/minute creatinine clearance for subjects with creatinine levels \> 1.5 × the institutional ULN
‣ Serum total bilirubin less than or equal to ≤ 1.5 × ULN or direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 × ULN
‣ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN except for subjects with liver metastases for whom ALT and AST should be ≤ 5× ULN
‣ International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy if PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
‣ Activated PTT (aPTT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulant
• Female patients of childbearing potential must have a negative pregnancy test documented at time of screening.
• Female patients who:
∙ Are postmenopausal for at least 1 year before the screening visit, OR
‣ Are surgically sterile, OR
‣ If they are of childbearing potential, agree to use a highly effective method of contraception from the time of signing the informed consent through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse The effects of lorlatinib on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
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∙ Postmenopausal (no menses in greater than or equal to 12 consecutive months).
‣ History of hysterectomy or bilateral salpingo-oophorectomy.
‣ Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
‣ History of bilateral tubal ligation or another surgical sterilization procedure.
‣ Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide.
• Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
⁃ Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
∙ Agree to completely abstain from heterosexual intercourse
∙ Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of lorlatinib administration.
⁃ Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of
⁃ ≤450 milliseconds (msec) in males or ≤470 msec in females.
⁃ Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
⁃ Ability to understand and the willingness to sign a written informed consent document.