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Lorlatinib in Combination with Ramucirumab for Treatment in Patients with Advanced ALK-rearranged Advanced Non-Small Cell Lung Cancer
Trial Status: active
This phase I/II trial studies the side effects and best dose of lorlatinib when given together with ramucirumab and to see how well it works in treating patients with non-small cell lung cancer (NSCLC) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and cancer has a change (fusion) involving the ALK gene (called ALK-rearranged). A fusion gene is made in the body when parts of two different genes join together. Lorlatinib is routinely used to treat ALK-rearranged NSCLC and works to prevent cancer spread by interfering with the growth of cancer cells, which are eventually destroyed by the body. Ramucirumab is a type of drug called a monoclonal antibody. Monoclonal antibodies are similar to the antibodies your body makes to fight infections caused by bacteria or viruses. Ramucirumab binds to a molecule called VEGF Receptor 2 (VGFR-2) that promotes the growth of cancer cells. Binding to this receptor may slow or stop the growth and spread of cancer. Giving lorlatinib in combination with ramucirumab may work better in treating patients with advanced ALK-rearranged NSCLC.
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%
Absolute neutrophil count (ANC) >=1.5 x 10^9/L
Platelets >=100 × 10^9/L
Hemoglobin >=9 g/dL
International normalized ratio (INR) =<1.5
Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) <1.5 x upper limit normal (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)
Aspartate aminotransferase (AST) =<3 x ULN
Alanine aminotransferase (ALT) =< 3 × ULN or =< 5 x ULN in the setting of liver metastases
Creatinine (Cr) =<1.5 ULN or creatinine clearance (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
Exclusion Criteria
Prior lorlatinib or ramucirumab exposure
Symptomatic, unstable brain metastasis requiring therapy with steroids or radiation therapy. Patients with clinically stable brain metastases (previously treated or untreated) 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 minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy
Less than 3 weeks since previous chemotherapy, 4 weeks since immunotherapy, and 2 weeks from any investigational therapy
Significant bleeding disorders or grade >=3 bleeding episode within 12 weeks prior to enrollment. Patients with history of gross hemoptysis (defined as bright red blood of >=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 of protocol therapy. Patients with thromboembolic events diagnosed >12 weeks prior to protocol therapy are eligible if on stable doses of anticoagulation as outlined above.
Venous port or catheter thrombosis or superficial venous thrombosis are not considered significant events
Gastrointestinal (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. New York Heart Association (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
Additional locations may be listed on ClinicalTrials.gov for NCT06007937.
I. To establish the maximum tolerated dose (MTD) and safety of combination of lorlatinib and ramucirumab in patients with advanced ALK-rearranged lung cancers. (Phase 1: safety run in)
II. To determine the 12-month progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 for patients with advanced lorlatinib ALK-rearranged lung cancers treated with lorlatinib and ramucirumab in the TKI-naive and the tyrosine kinase inhibitors (TKI)-treated setting using two patient cohorts:
IIa. Cohort 1: patients who have not received a prior ALK inhibitor;
IIb. Cohort 2: patients with disease progression on a second-generation ALK. (Phase 2)
SECONDARY OBJECTIVES:
I. Overall response rate (ORR)
II. Overall survival (OS)
III. Intracranial PFS
IV. Intracranial ORR
V. To further characterize the tolerability of the combination
CORRELATIVE/EXPLORATORY OBJECTIVES:
I. To identify genomic markers associated with response to lorlatinib and ramucirumab treatment, using next-generation sequencing (NGS) of pre-treatment archival samples.
II. To determine whether early circulating-tumor deoxyribonucleic acid (ctDNA) clearance at 6 and 12 weeks is associated with prolonged PFS in patients treated with the combination.
OUTLINE: This is a phase I, dose-escalation study of lorlatinib followed by a phase II study.
Patients receive lorlatinib orally (PO) once daily (QD) and ramucirumab intravenously (IV) over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computerized tomography (CT) and magnetic resonance imaging (MRI) and blood sample collection throughout the trial.
After completion of study treatment, patients are followed up at 30 days then up to 1 year.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center