PCSK9 Inhibitor and PD-1 Inhibitor in Patients With Metastatic, Refractory To Prior Anti PD-1 Non-small Cell Lung

Study Overview
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Brief Summary
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PCSK9 mediates immune checkpoint blockade resistance by downregulating tumor cell surface MHC class 1 molecules. This study will evaluate if combining the anti-PCSK9 antibody alirocumab with the anti-PD-1 antibody cemiplimab can generate anti-tumor activity and clinical responses in patients with metastatic lung cancer who have progressed on first line immune checkpoint blockade therapy.

Official Title
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A Phase II Study of PCSK9 Inhibitor Alirocumab and PD-1 Inhibitor Cemiplimab in Patients With Metastatic, Refractory To Prior Anti PD-1 Non-small Cell Lung Cancer: TOP2201

Conditions
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Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Combination Product: Alirocumab and Cemiplimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented recurrent and/or metastatic non-small cell lung cancer 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 ECOG Performance Status 0 or 1 Signed written informed consent Minimum of 4 weeks from any other experimental anti-cancer therapies or prior PD-1 treatment Meet all the laboratory criteria per protocol Exclusion Criteria: Prior treatment with PCSK9 inhibitors Cardiac issues including MI, uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by medications. Uncontrolled diabetes mellitus, defined as HbA1c > 10 Major surgery less than 4 weeks prior to study enrollment Another malignant condition diagnosed within 3 years of study enrollment 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 developed an immune checkpoint blockade related immune adverse event that was refractory to steroids and required additional systemic immunosuppressive medication. Known history of HIV seropositivity or known acquired immunodeficiency syndrome (AIDS) Additional exclusion criterion as per listed in the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Combination therapy involving anti-PCSK9 antibody alirocumab with the anti-PD-1 antibody cemiplimab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alirocumab and Cemiplimab<br>Combination of anti-PCSK9 antibody alirocumab with the anti-PD-1 antibody cemiplimab | Combination Product: Alirocumab and Cemiplimab<br>* Combination of PCSK9 inhibitor Alirocumab 150mg SC q2weeks and PD-I inhibitor Cemiplimab 350mg IV q3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate associated with combination of alirocumab and cemiplimab | Ascertain the response rate associated with alirocumab and cemiplimab, with 95% confidence intervals. Response rate is defined as the proportion of treated subjects with a complete or partial response per RECIST 1.1 criteria. All patients who receive at least one dose of alirocumab and cemiplimab will be considered for the primary outcome analysis | Day 1 of treatment until the date of first documented progression or date of death, whichever comes first, assessed up to 110 weeks per RECIST 1.1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of the combination regimen | Toxicity analysis will be performed on a continual basis following CTC V 5.0 criteria | Day 1 of treatment until 30 days post last dose | 
| Progression Free Survival | Progression Free Survival will be assessed utilizing RECIST 1.1 criteria | Day 1 of treatment until the date of first documented progression or date of death, whichever comes first, assessed up to 110 weeks | 
| Overall survival | Patients will be followed till death or off study due to any other reason | Day 1 of treatment until death or off study due to any other reason whichever comes first, assessed up to 110 weeks |