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Alirocumab in Combination with Cemiplimab for the Treatment of Stage IV Non-Small Cell Lung Cancer in Patients that have Progressed on Prior PD-1 Inhibitor, TOP 2201
Trial Status: active
This phase II trial tests the safety and effectiveness of alirocumab (a PCSK9 inhibitor) in combination with cemiplimab (a PD-1 inhibitor) in treating patients with stage IV non-small cell lung cancer that have progressed on prior anti-PD-1 therapy. Alirocumab injection is in a class of medications called proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor monoclonal antibodies. PCSK9 inhibitors are a type of cholesterol-lowering medicine. It works by lowering your levels of low-density lipoprotein cholesterol (LDL-C), also known as “bad cholesterol.” Cemiplimab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. PD-1 inhibitors and PD-L1 inhibitors are a group of anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Combing the anti-PCSK9 antibody alirocumab with the anti-PD-1 antibody cemiplimab may help to generate anti-tumor activity and clinical responses in participants with metastatic lung cancer that have progressed on prior PD-1 inhibitors.
Inclusion Criteria
Histologically and/or cytologically documented recurrent and/or metastatic stage IV non-small cell lung cancer (NSCLC)
Progression after prior PD-1 directed therapy (as monotherapy or in combination with chemotherapy and/or anti-CTLA4, or anti-VEGF agents) – defined as investigator assessed progression from prior treatment.
If molecularly altered NSCLC including EGFR, ALK, ROS1, MET exon 14, RET, BRAF, NTRK, progression on prior targeted therapy is required.
Measurable disease by RECIST 1.1. Tumor lesions in a previously irradiated area are considered measurable IF progression has been demonstrated in such lesions after radiation
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
Minimum of 4 weeks from any other experimental anti-cancer therapies or prior PD-1 treatment
Age > 18 years
Signed written informed consent including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines
Absolute neutrophil count (ANC) >= 1500 per uL
Platelets >= 100,000 per uL
Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
Serum creatinine =<1.5 x upper limit of normal (ULN) OR creatinine clearance using Cockcroft-Gault formula >= 40 mL/min for subject with creatinine levels > 1.5 x institutional ULN
Serum total bilirubin =< 1.5 x ULN OR bilirubin < 3.0 ml/dL and direct bilirubin =< ULN for subject with Gilbert’s syndrome with total bilirubin levels > 1.5 ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 X ULN for subject with documented liver metastases
Exclusion Criteria
Prior treatment with PCSK9 inhibitors
Myocardial infarction having occurred less than 6 months prior to study enrollment, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications. Patients with coronary artery disease (CAD) recently treated with surgery and/or stent greater than 6 months prior to enrollment, and if stable without symptomatic angina pectoris or active ischemia are eligible
Uncontrolled diabetes mellitus, defined as hemoglobin (Hb)A1c > 8.5
Major surgery less than 4 weeks prior to study enrollment
Known history of human immunodeficiency virus (HIV) seropositivity or known acquired immunodeficiency syndrome (AIDS)
Another malignant condition diagnosed within 3 years of study enrollment. Exceptions include non-invasive superficial cancers including squamous cell in situ of skin and Gleason 6 prostate adenocarcinoma with very low or low risk prostate cancer intact; or definitively treated prostate cancer determined to be in remission
Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
Extracranial palliative radiation within 2 weeks of study enrollment
Receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent with the following exceptions:
* Intermittent steroids (not to exceed prednisone 10 mg every day or equivalent dosing) may be used on an as-needed basis (e.g., treatment for chemotherapy-related nausea, anorexia, and fatigue)
* Physiologic replacement doses of steroids due to adrenal insufficiency for any reason
* Topical, inhaled, or intra-articular corticosteroids
Known autoimmune conditions requiring systemic immune suppressive therapy other than prednisone less than or equal to 10 mg
Symptomatic brain or leptomeningeal metastases, including patients who continue to require glucocorticoids and/or anti-seizure therapy for brain or leptomeningeal metastases. Treated, asymptomatic metastases are permitted provided the patient has completed radiation at least 2 weeks prior to day 1 and has been off steroids for at least 1 week prior to day 1 of study drug. Stable (MRI or CT with contrast performed > 4 weeks apart), untreated brain metastases are permitted if patient does not require steroids or anti-seizure therapy
History of interstitial pneumonitis from any cause
Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, or in the opinion of the investigator any physiological state likely to cause systemic or regional hypoxemia)
Intolerance to prior PD-1/L1 treatment including discontinuation for severe or recurrent severe toxicity (including myocarditis or other myocardiotoxity, encephalitis, colitis, diarrhea, pancreatitis, hypo/hyperthyroidism, hypopituitarism, adrenal insufficiency, rash, autonomic neuropathy, myasthenia gravis, Guillain-Barre, myositis/polymyositis, hepatitis, type 1 diabetes, thrombocytopenia) or known anaphylaxis/allergy or severe hypersensitivity to Chinese hamster ovary (CHO) products or developed an immune checkpoint blockade related immune adverse event that was refractory to steroids and required additional systemic immunosuppressive medication. Prior topical steroids for rashes and oral steroids with control of prior immune-mediated adverse event are permitted
Additional locations may be listed on ClinicalTrials.gov for NCT05553834.
I. To study the clinical activity (response rate as assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of PCSK-9 inhibitor alirocumab in combination with cemiplimab in patients with locally advanced or metastatic non-small cell lung cancer who have progressed on prior therapy with an anti-PD1/L1 agent.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of the combination regimen.
II. To evaluate secondary efficacy endpoints of the combination regimen;
IIa. Disease control rate (stable disease [SD], partial response [PR], and complete response [CR]);
IIb. Complete response rates;
IIc. Progression free survival per RECIST 1.1 criteria;
IId. Overall survival;
IIe. Duration of responses.
EXPLORATORY OBJECTIVES:
I. To evaluate the pharmacodynamic marker of the change in low-density lipoprotein (LDL) cholesterol levels measured in serial plasma collections while on treatment with alirocumab.
OUTLINE:
Patients receive alirocumab subcutaneously (SC) every 2 weeks (Q2W) and cemiplimab intravenously (IV) every 3 weeks (Q3W) of each cycle. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) at baseline, computed tomography (CT) scans at baseline, every cycle, at restaging, and during follow-up, and collection of blood samples at screening, on day 1 of cycles 1 and 2, at disease progression or discontinuation of study treatment, and during follow-up.
After completion of the study treatment, patients are followed up at 28 days and every 3 months for up to 5 years after the last patient is enrolled or until the study is closed (whichever comes first).
