A Study of Lorlatinib in Combination With Ramucirumab in People With Lung Cancer

Inclusion Criteria

• •Written informed consent
• •Age \>18 years old
• •Metastatic or recurrent, biopsy-proven non-small cell lung cancer
• •ALK fusion identified by next generation sequencing (NGS) or IHC on material obtained from tumor or plasma
• •Measurable (RECIST 1.1) indicator lesion not previously irradiated
• •Karnofsky performance status (KPS) ≥ 70%
• •Adequate organ function defined as follows: ANC ≥1.5 × 10\^9 /L, platelets ≥100 × 10\^9/L, hemoglobin ≥ 9 g/dL, INR ≤ 1.5, PTT or aPTT \<1.5x ULN, total bilirubin ≤ 1.5 × ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted), AST ≤ 3 × ULN, ALT ≤ 3 × ULN or ≤ 5 x ULN in the setting of liver metastases, Cr ≤1.5 ULN or CrCl ≥ 40 mL/min. If Cr is
• •≥ 1.5x ULN, a 24-hr urine collection to calculate creatinine clearance must be performed
• •°The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (UA); if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate \<1000 mg of protein in 24 hours to allow participation in this protocol).
• •Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin for a minimum of 14 days prior to trial enrollment without signs of active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor invading major vessels or known varices). Patients on warfarin must have an INR ≤ 3.0
• •Patients must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5 Grade ≤1) from the acute effects of prior therapy, except for residual alopecia or peripheral neuropathy (up to grade 2 allowed)prior to start of therapy
• •Patients in cohort 1 will be treatment-naïve in the metastatic setting. Prior treatment with adjuvant chemotherapy is allowed
• •Patients in cohort 2 will have progressed or be intolerant of at least one second generation ALK TKI, including alectinib, brigatinib, or ceritinib.
• •Patients may have received multiple ALK TKIs as well as chemotherapy, but one of these treatments must have been with a second-generation ALK TKI.
• •Because the teratogenicity of ramucirumab is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods).
• •Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of protocol therapy.
• •GI perforation and/or fistula or bowel obstruction within 6 months or risk factors for perforation prior to enrollment
• •Child-Pugh B or greater cirrhosis or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
• •Uncontrolled hypertension, defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg, prior to initiating study treatment, despite hypertensive intervention
• •Serious or non-healing wound, ulcer or bone fracture within 28 days of enrollment
• •Radiologically documented evidence of major blood vessel invasion or encasement by cancer or radiographic evidence of intratumor cavitation
• •Active systemic bacterial infection (requiring intravenous \[IV\] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\]. Screening is not required for enrollment.
• •Arterial thrombotic event or arterial thromboembolic event, including myocardial infarction, unstable angina, congestive heart failure ≥ NYHA class III, cerebrovascular accident or transient ischemic attack, within 6 months prior to enrollment
• •Planned elective or major surgery during the trial
• •Chronic therapy with any of the following within 7 days of enrollment:
• •* Antiplatelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide)
• •* Aspirin up to 325 mg/day is permitted
• •Serious uncontrolled medical disorders or psychological conditions that would, in the opinion of the investigator, limit the patient's ability to complete the study or sign an informed consent document
• •Patients with unavoidable strong CYP3A inducer or inhibitor use (see table 15.4 for list of agents)