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Thoracic Radiotherapy and Inhibition of PD-1 and LAG-3 for Locally Advanced Non-Small Cell Lung Cancer

ConditionsNSCLCLocally Advanced
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorMontefiore Medical Center

About this trial

Determine anti-tumor efficacy by characterizing response rates on positron emission tomography (PET) following three cycles of induction immunotherapy with cemiplimab and fianlimab without chemotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Previously untreated and biopsy-proven NSCLC, with measurable disease (at least 1 unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of the following stages: (prior resection or stereotactic radiotherapy for early-stage disease is allowed)

AJCC version 8 Stage II disease, medically or technically unresectable

AJCC version 8 Stage III disease, eligible for non-surgical treatment

Determination of PD-L1 expression on pretreatment tumor specimen using a clinically validated assay

Disqualifiers

Not a woman of childbearing potential (WOCBP) as defined in the Appendix

A WOCBP who agrees to follow the contraceptive guidance in the Appendix during the treatment period and for at least 6 months (180 days) after the last dose of study treatment with cemiplimab and fianlimab

A WOCBP who agrees to follow the contraceptive guidance in the Appendix and for at least 6 months after the last dose of chemotherapy or as specified in FDA prescribing labels (e.g. 14 months after the last dose of cisplatin)

A male participant must agree to use contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period

Trial design

Design model

Parallel

Treatments tested in this trial

  • Cemiplimab

    Drug

    Human IgG anti-PD-1 monoclonal antibody approved for treatment of advanced NSCLC with PD-L1 TPS ≥ 50% as monotherapy and in combination with chemotherapy

  • Fianlimab

    Drug

    Human IgG anti-lymphocyte activation gene 3 (LAG-3) monoclonal antibody, which is expressed by various immune cells, and regulates effector T-cell activation and responses. LAG-3 inhibition restores the effector function of exhausted T cells, enhancing their ability to attack tumor cells. Fianlimab is currently under investigation in several clinical studies involving NSCLC (NCT05800015, NCT03916627, NCT05785767).

  • Radiotherapy

    Radiation

    Thoracic radiotherapy. Conventionally fractionated 1.8-2.0 Gray (Gy) per day. Adaptive radiotherapy will not be performed unless difficulty with patient setup or changes in internal patient anatomy require repeating the CT simulation procedure

  • Platinum Doublet Chemotherapy (PDC)

    Drug

    Acceptable histology-specific PDC regimens include carboplatin plus paclitaxel or nab-paclitaxel (any histology), carboplatin/cisplatin plus pemetrexed (nonsquamous), carboplatin/cisplatin plus etoposide (any histology), and carboplatin/cisplatin plus docetaxel or gemcitabine (squamous). Carboplatin can be used instead of cisplatin after cycle 1 in cases of cisplatin-induced neuro-/oto-/nephrotoxicity as long as the patient remains eligible for chemoradiotherapy. Weekly radiosensitizing PDC will be recommended for PD-L1 TPS \<50% patients during RT but is not required.

Treatment groups

76 Participants
are divided into 2 treatment groups
Group A: Cohort 1: PD-L1 (TPS ≥ 50%)Experimental treatment 3 interventions
Group B: Cohort 2: PD-L1 (TPS < 50%)Experimental treatment 4 interventions

Trial outcomes

Primary outcomes

1

Objective Response Rate (ORR) to induction IO therapy

ORR to induction therapy will be evaluated by fluorodeoxyglucose (FDG) FDG-PET scan using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria. Pre-and post-treatment maximum standardized uptake value (SUV) levels following PERCIST criteria will be assessed. Specifically, the percentage of patients who experience either a complete metabolic response (CMR) or partial metabolic response (PMR) based on changes in FDG uptake will be determined and quantified using the following calculation (PMR+CMR/Sample Size). All participants who initiate study therapy will be analyzed for ORR. Participants who do not undergo response rate evaluation for any reason will be categorized as non-responders. Response rates in each study cohort will be summarized and reported using counts and percentages. 95% Clopper-Pearson confidence intervals will be calculated. ORR based on PET are more accurate predictors of long-term clinical outcomes than computed tomography (CT).

Time frame
Following 3 cycles (each cycle is ~3 weeks) of induction IO therapy, approximately 10 weeks overall

Secondary outcomes

1

Dose-limiting toxicity (DLT)

DLT will be defined as the occurrence of any of the following adverse events (AEs) that, in the opinion of the PI, significantly interferes with the patient's optimal management: * CTCAE v5.0 Grade 3-4 or recurrent grade 2 pneumonitis; Grade 4 diarrhea/colitis; Grade 3-4 myocarditis; or Grade 3 thrombocytopenia with clinically significant bleeding * Febrile neutropenia (any grade) * Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 times upper limit of normal (ULN) with concurrent increase in total bilirubin \>2 times ULN, without evidence of cholestasis or alternative explanations such as viral hepatitis, disease progression in the liver, etc. (i.e., Hy's Law). * any death not clearly due to the underlying disease or extraneous causes * any toxicity requiring permanent discontinuation of study drug(s). DLTs will be assessed as a dichotomous (Yes/No) measure. Results will be summarized and reported by study arm using basic descriptive statistics.

Time frame
From initiation of study immunotherapy until 4 weeks following completion of radiotherapy, up to 17 weeks total

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Montefiore Medical Center

Lead sponsor

Regeneron Pharmaceuticals

Collaborator

Henry Ford Health System

Collaborator

NYU Langone Health

Collaborator

University of Michigan

Collaborator

Source ClinicalTrials.gov
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