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 materialobtained 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 anddirect bilirubin within normal limits are permitted), AST ≤ 3 × ULN, ALT ≤ 3 × ULNor ≤ 5 x ULN in the setting of liver metastases, Cr ≤1.5 ULN or CrCl ≥ 40 mL/min. IfCr is

≥ 1.5x ULN, a 24-hr urine collection to calculate creatinine clearance must beperformed

°The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (UA); ifurine dipstick or routine analysis is ≥2+, a 24-hour urine collection for proteinmust demonstrate <1000 mg of protein in 24 hours to allow participation in thisprotocol).

• Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulantor low molecular weight heparin for a minimum of 14 days prior to trial enrollmentwithout signs of active bleeding or pathological condition that carries a high riskof bleeding (eg, tumor invading major vessels or known varices). Patients onwarfarin 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 residualalopecia 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. Priortreatment with adjuvant chemotherapy is allowed

• Patients in cohort 2 will have progressed or be intolerant of at least one secondgeneration ALK TKI, including alectinib, brigatinib, or ceritinib.

• Patients may have received multiple ALK TKIs as well as chemotherapy, but one ofthese treatments must have been with a second-generation ALK TKI.

• Because the teratogenicity of ramucirumab is not known, the patient, if sexuallyactive, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods).

• Female patients of childbearing potential must have a negative serum pregnancy testwithin 7 days prior to first dose of protocol therapy.

Exclusion Criteria:

• Prior lorlatinib or ramucirumab exposure

• Symptomatic, unstable brain metastasis requiring therapy with steroids or radiationtherapy. Patients with clinically stable brain metastases (previously treated oruntreated) are eligible

• Women who are breastfeeding or pregnant

• Major radiotherapy within 2 weeks of starting treatment on protocol

• Major surgery within 4 weeks of starting treatment on protocol or minorsurgery/subcutaneous venous access device placement within 7 days prior to the firstdose of protocol therapy

• Less than 3 weeks since previous chemotherapy, 4 weeks since immunotherapy, and 2weeks from any investigational therapy

• Significant bleeding disorders or grade ≥3 bleeding episode within 12 weeks prior toenrollment. Patients with history of gross hemoptysis (defined as bright red bloodof ≥1/2 teaspoon) within 8 weeks prior to enrollment will be excluded

• New or history of diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE)or other significant thromboembolic event in the 12 weeks prior to first dose ofprotocol therapy. Patients with thromboembolic events diagnosed >12 weeks prior toprotocol therapy are eligible if on stable doses of anticoagulation as outlinedabove. Venous port or catheter thrombosis or superficial venous thrombosis are notconsidered significant events

• GI perforation and/or fistula or bowel obstruction within 6 months or risk factorsfor perforation prior to enrollment

• Child-Pugh B or greater cirrhosis or cirrhosis (any degree) and a history of hepaticencephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinicallymeaningful ascites is defined as ascites from cirrhosis requiring diuretics orparacentesis

• Uncontrolled hypertension, defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mmHg, 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 bycancer or radiographic evidence of intratumor cavitation

• Active systemic bacterial infection (requiring intravenous [IV] antibiotics at timeof initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity with known active hepatitis Bor C [for example, hepatitis B surface antigen positive]. Screening is not requiredfor enrollment.

• Arterial thrombotic event or arterial thromboembolic event, including myocardialinfarction, unstable angina, congestive heart failure ≥ NYHA class III,cerebrovascular accident or transient ischemic attack, within 6 months prior toenrollment

• 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, oranagrelide)

• Aspirin up to 325 mg/day is permitted

• Serious uncontrolled medical disorders or psychological conditions that would, inthe opinion of the investigator, limit the patient's ability to complete the studyor sign an informed consent document

• Patients with unavoidable strong CYP3A inducer or inhibitor use (see table 15.4 forlist of agents)