TOP 2301: Neoadjuvant Chemo for NSCLC

• ClinicalTrials.gov Identifier: NCT06385262
• Recruitment Status: Not yet recruiting
• First Posted: April 26, 2024
• Last Update Posted: April 29, 2024
• Sponsor: Duke University
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Neal Ready, Duke University

Tracking Information

• First Submitted Date: April 22, 2024
• First Posted Date: April 26, 2024
• Last Update Posted Date: April 29, 2024
• Estimated Study Start Date: July 1, 2024
• Estimated Primary Completion Date: June 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2024)

Compare pathologic complete response (pCR) rate for neoadjuvant chemotherapy plus cemiplimab versus chemotherapy, cemiplimab, and alirocumab. [ Time Frame: 2 years ]

Pathologic complete response (pCR) is defined as a lack of all signs of cancer in tissue samples removed during surgery or biopsy after neoadjuvant therapy.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 25, 2024)

• Assess the preliminary efficacy of chemotherapy and cemiplimab with alirocumab as determined by objective response rate (ORR) [ Time Frame: 2 years ]
  ORR is defined as complete response (CR) + major pathologic response (MPR) + partial response (PR)
• Assess the preliminary efficacy of chemotherapy and cemiplimab with alirocumab as determined by disease-free survival (DFS) [ Time Frame: 2 years ]
  Disease-free survival (DFS) is defined as the time from randomization to disease recurrence (first disease recurrence or death, whichever comes first) after surgery
• Assess the preliminary efficacy of chemotherapy and cemiplimab with alirocumab as determined by overall survival (OS) [ Time Frame: 2 years ]
  Overall survival (OS) is the length of time that a patient lives following treatment
• Determine the safety of neoadjuvant chemotherapy and cemiplimab with alirocumab in early-stage non-small cell lung cancer (NSCLC) [ Time Frame: 2 years ]
  Safety will be determined by evaluating the severe adverse events rate for the experimental therapy.
• Determine the tolerability of neoadjuvant chemotherapy and cemiplimab with alirocumab in early-stage non-small cell lung cancer (NSCLC) [ Time Frame: 2 years ]
  Tolerability will be determined by evaluating the severe adverse events rate for the experimental therapy.

Original Secondary Outcome Measures (submitted: April 22, 2024)

• Assess the preliminary efficacy of chemotherapy and cemiplimab with alirocumab as determined by objective response rate (ORR) [ Time Frame: 2 years ]
  ORR is defined as complete response (CR) + major pathologic response (MPR) + partial response (PR)
• Assess the preliminary efficacy of chemotherapy and cemiplimab with alirocumab as determined by disease-free survival (DFS) [ Time Frame: 2 years ]
  Disease-free survival (DFS) is defined as the time from randomization to disease recurrence (first disease recurrence or death, whichever comes first) after surgery
• Assess the preliminary efficacy of chemotherapy and cemiplimab with alirocumab as determined by overall survival [ Time Frame: 2 years ]
  Overall survival is the length of time that a patient lives following treatment
• Determine the safety of neoadjuvant chemotherapy and cemiplimab with alirocumab in early-stage non-small cell lung cancer [ Time Frame: 2 years ]
  Safety will be determined by evaluating the severe adverse events rate for the experimental therapy.
• Determine the tolerability of neoadjuvant chemotherapy and cemiplimab with alirocumab in early-stage non-small cell lung cancer [ Time Frame: 2 years ]
  Tolerability will be determined by evaluating the severe adverse events rate for the experimental therapy.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TOP 2301: Neoadjuvant Chemo for NSCLC
• Official Title: Safety, Efficacy, and Tumor Immune Microenvironment Changes With Neoadjuvant Chemotherapy and Cemiplimab With or Without Alirocumab in Stage 1B-3A Non-Small Cell Lung Cancer: TOP 2301

Brief Summary

In this open-label, two-arm, randomized phase 2 clinical trial, patients with clinical stage 1B-3A non-small cell lung cancer (NSCLC) will receive neoadjuvant chemotherapy and cemiplimab every 3 weeks for 3 cycles with or without alirocumab every 4 weeks prior to surgery.

Eligible patients will be randomized with equal allocation to two treatment groups. Permuted block randomization algorithm will be used for treatment assignment with stratification factors: stage (1B, 2A, 2B, 3A), and performance status (0 vs. 1).

The study hypothesis is that the addition of alirocumab to neoadjuvant chemoimmunotherapy will make tumor cells more immunogenic to cytotoxic T cells, resulting in an increase in complete pathologic responses in surgically resected tumor.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non Small Cell Lung Cancer

Intervention

• Drug: Alirocumab
  300 mg subcutaneously every 4 weeks prior to surgery
• Drug: Cemiplimab
  350mg IV every 3 weeks prior to surgery
• Drug: Chemotherapy
  Treating provider's choice of FDA approved platinum doublet chemotherapy IV every 3 weeks prior to surgery

Study Arms

• Experimental: Arm A
  Chemotherapy and cemiplimab (PD-1 inhibitor) every 3 weeks for 3 cycles with alirocumab (PCSK9 inhibitor) every 4 weeks prior to surgery
  Interventions:

  • Drug: Alirocumab
  • Drug: Cemiplimab
  • Drug: Chemotherapy
• Experimental: Arm B
  Chemotherapy and cemiplimab (PD-1 inhibitor) every 3 weeks for 3 cycles without alirocumab (PCSK9 inhibitor) prior to surgery
  Interventions:

  • Drug: Cemiplimab
  • Drug: Chemotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 22, 2024): 126
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2028
• Estimated Primary Completion Date: June 30, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age ≥ 18 years.
2. Histological/cytological diagnosis of non-small cell lung cancer (NSCLC). Patient is eligible to enroll in the study based on clinical suspicion of NSCLC but are required to have a histological diagnosis of NSCLC in order to be eligible to receive treatment on study.
3. Clinical stage IB, IIA/IIB, or III (N0-2) amenable to surgical resection.
4. Primary tumor size of ≥ 3 cm (for all clinical stages to insure adequate tumor for correlative studies).
5. Agrees to research blood collections for study.
6. Deemed a surgical candidate.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. No prior chemotherapy, radiation therapy or biologic/targeted therapy for current diagnosis of lung cancer.
9. Measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.
10. No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. Cancers that are in-situ are not considered invasive.
11. Signed written informed consent including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines.
12. Sexually active males and females of reproductive potential must agree to use an appropriate contraceptive method during the study and for 120 days following the last dose of study drug.
13. Females of childbearing potential must test negative for pregnancy within 48 hours prior to any initial study procedure based on a serum pregnancy test. (If subject uses appropriate contraceptive methods from the time of the initial serum pregnancy test, then the subsequent pregnancy test can be done within 72 hours prior to start of study treatment. If appropriate contraceptive measures are not begun immediately with the first serum pregnancy test, then subsequent serum pregnancy tests must be done within 48 hours prior to the start of study treatment.)

14. Adequate organ function defined as:

    1. Absolute neutrophil count (ANC) ≥ 1500 per uL
    2. Platelets ≥ 100,000 per uL
    3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or growth factor dependency (within 7 days of assessment)
    4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN
    5. Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    6. Aspartate aminotransferase (AST) [serum glutamic-oxaloacetic transaminase (SGOT)] and alanine aminotransferase (ALT) [glutamic-pyruvic transaminase (SGPT)]≤ 2.5 x ULN
    7. Albumin ≥ 2.5 mg/dL
    8. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy and within therapeutic range of intended use of anticoagulants
    9. Activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN unless subject is receiving anticoagulant therapy and within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

1. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment.
2. Participants with known EGFR mutations, ALK translocation, or ROS1 translocation. If testing is done, an FDA-approved assay should be used.
3. Known history of active TB (Bacillus Tuberculosis).
4. Hypersensitivity to alirocumab or any of its excipients.
5. Concurrent administration of any other anti-tumor therapy.
6. Prior therapy with an anti-PD-1, anti-PD-L-1, or anti-PD-L2 agent.
7. Therapy with an anti-PCSK9 agent within 90 days of study entry.
8. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
9. Inability to comply with protocol or study procedures.
10. Active infection requiring antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
11. Known history of, or any evidence of active, non-infectious pneumonitis.

12. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or HCV infection; or diagnosis of immunodeficiency. Exceptions:

    1. Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted.
    2. Patients with HBV (hepatitis B surface antigen positive) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction (PCR) that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted.
    3. Patients who are HCV antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
13. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc.) is not considered a form of systemic treatment. Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g. Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis).
14. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
15. Known additional invasive malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy in situ cervical cancer.
16. 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 study treatment.
17. Major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious concomitant disorders that in the opinion of the investigator would compromise the safety of the patient or compromise the patient's ability to complete the study.

18. Any non-oncology, live vaccine therapy used for prevention of infectious diseases within 30 days prior to start of study treatment.

    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed. Coronavirus Disease 2019 (COVID-19) vaccines are also allowed.

19. 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 treated with surgery and/or stent > 6 months ago, if stable without symptomatic angina pectoris, active ischemia are eligible.
20. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either psychiatric or physical (e.g., infectious) illness.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Neal Ready, MD, PhD; +1 919 681 6932; neal.ready@duke.edu

Contact: Monika Anand, PhD; +1 919 681 8838; monika.anand@duke.edu

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT06385262
• Other Study ID Numbers: Pro00114645
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Neal Ready, Duke University
• Original Responsible Party: Same as current
• Current Study Sponsor: Duke University
• Original Study Sponsor: Same as current
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Principal Investigator: Neal Ready, MD, PhD; Duke University

• PRS Account: Duke University
• Verification Date: April 2024