Study to Test the Safety and How Radium-223 Dichloride an Alpha Particle-emitting Radioactive Agent Works in Combination With Pembrolizumab an Immune Checkpoint Inhibitor in Patients With Stage IV Non-small Cell Lung Cancer With Bone Metastases

Study Overview
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Brief Summary
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The purpose of the study is to determine the safety and test the efficacy of the combination of radium-223 dichloride and pembrolizumab in patients with stage IV non-small cell lung cancer (NSCLC) with bone metastases who either have not received any systemic therapy for their advanced disease or have progressed on prior immunologic checkpoint blockade with antibodies against the programmed cell death protein-(ligand) 1 (PD-1/PD-L1). In this study researchers want to measure tumor shrinkage in response to treatment and how long that shrinkage lasts and gather information on safety. Pembrolizumab is an immunologic checkpoint blocker that promotes an immune response against the tumor. Radium-223 dichloride is an alpha particle-emitting radioactive agent which kills cancer cells.

Official Title
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An Open-label, Multicenter, Phase 1/2 Study of Radium-223 Dichloride in Combination With Pembrolizumab in Participants With Stage IV Non-small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of stage IV NSCLC. Phase 2 Cohort 1: No Epidermal Growth Factor Receptor (EGFR) / v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or anaplastic lymphoma kinase (ALK)/ROS1 rearrangement. Treatment naïve (no prior systemic therapy) for their metastatic NSCLC. Phase 2 Cohort 2: progression on prior treatment with an immune checkpoint inhibitor inhibitor. Prior treatment with platinum-based chemotherapy in combination or in sequence in line with local standard of care. Phase 1 includes participants meeting either Cohort 1 or Cohort 2 criteria. Measurable disease per RECIST v1.1. At least 2 skeletal metastases. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Adequate bone marrow and organ function. Participants must be on a bone health agent (BHA) treatment, such as bisphosphonates or denosumab treatment unless such treatment is contraindicated or not recommended per investigator's judgement. Exclusion Criteria: Previous or concurrent cancer within 3 years prior to enrollment. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor. Phase 2 Cohort 2: was discontinued from that treatment due to a Grade 3 or higher immune-related AEs (irAEs). Known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Active autoimmune disease that has required systemic treatment in the past 2 years. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Known history or presence of osteonecrosis of jaw. Ongoing infection >Grade 2 NCI-CTCAE v.5.0 requiring systemic therapy. Significant acute GI disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or ≥ NCI-CTCAE v.5.0 Grade 2 diarrhea of any etiology. History of osteoporotic fracture. Prior treatment with radium-223 dichloride or any therapeutic radiopharmaceutical. Prior radiotherapy within 21 days of planned start of study treatment.

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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Radium-223+Pembrolizumab<br>Participants will receive radium-223 dichloride every 6 weeks in combination with pembrolizumab every 3 weeks | Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)<br>* Intravenous (IV) injection, every 6 weeks for up to 6 administrations<br>Drug: Pembrolizumab<br>* IV infusion, every 3 weeks for a maximum of up to 35 administrations<br>|
| Experimental: Phase 2 Cohort 1: Radium-223+Pembrolizumab<br>Participants will receive radium-223 dichloride every 6 weeks in combination with pembrolizumab every 3 weeks | Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)<br>* Intravenous (IV) injection, every 6 weeks for up to 6 administrations<br>Drug: Pembrolizumab<br>* IV infusion, every 3 weeks for a maximum of up to 35 administrations<br>|
| Active Comparator: Phase 2 Cohort 1: Pembrolizumab alone<br>Participants will receive pembrolizumab every 3 weeks | Drug: Pembrolizumab<br>* IV infusion, every 3 weeks for a maximum of up to 35 administrations<br>|
| Experimental: Phase 2 Cohort 2: Radium-223+Pembrolizumab<br>Participants will receive radium-223 dichloride every 6 weeks in combination with pembrolizumab every 3 weeks | Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)<br>* Intravenous (IV) injection, every 6 weeks for up to 6 administrations<br>Drug: Pembrolizumab<br>* IV infusion, every 3 weeks for a maximum of up to 35 administrations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) in Phase 1 |  | Until 30 days after the last dose of the study intervention (up to 3 years) | 
| Number of participants with dose limiting toxicities (DLTs) in Phase 1 |  | Up to 6 weeks | 
| Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in Phase 2 | ORR is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) during the course of the study. | Up to 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR per RECIST v1.1 in Phase 1 |  | Up to 5 years | 
| Duration of response (DoR) per RECIST v1.1 in Phase 1 | DoR is defined as the time interval from the date of first response (CR or PR) to the date of disease progression or death, whichever comes first. | Up to 5 years | 
| Disease control rate (DCR) per RECIST v1.1 in Phase 1 | DCR is defined as the percentage of participants with CR or PR, or SD for at least 6 weeks during the course of the study. | Up to 5 years | 
| DoR per RECIST v1.1 in Phase 2 |  | Up to 5 years | 
| DCR per RECIST v1.1 in Phase 2 |  | Up to 5 years | 
| Progression free survival (PFS) per RECIST v1.1 in Phase 2 | PFS is defined as the time period until the date of radiological progression or death whichever occurs first. | Up to 5 years | 
| Overall survival (OS) in Phase 2 | OS is defined as the time period until the death due to any cause. | Up to 5 years | 
| Number of participants with AE in Phase 2 |  | Until 30 days after the last dose of the study intervention (up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC