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

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

The purpose of the study was 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 had not received any systemic therapy for their advanced disease or had progressed on prior immunologic checkpoint blockade with antibodies against the programmed cell death protein-(ligand) 1 (PD-1/PD-L1). In this study researchers wanted to measure tumor shrinkage in response to treatment and how long that shrinkage lasted and gathered 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.

Study Overview

• Status: Terminated
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Radium-223 dichloride (Xofigo, BAY 88-8223); Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • UZ Gent
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Nederlands Kanker Instituut
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain, 08035
    • Ciutat Sanitaria i Universitaria de la Vall d'Hebron
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
• United States
  • California
    • San Marcos, California, United States, 92069
      • Ccare San Marcos Cancer Center & Urology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Radium-223+Pembrolizumab; Participants received radium-223 dichloride at 55 kBq/kg every 6 weeks in combination with pembrolizumab every 3 weeks.	Drug: Radium-223 dichloride (Xofigo, BAY 88-8223); 55 kBq/kg, intravenous (IV) injection, every 6 weeks for up to 6 administrations; Drug: Pembrolizumab; 200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations
Experimental: Phase 2 Cohort 1: Radium-223+Pembrolizumab; Participants was planned to receive radium-223 dichloride at the maximum tolerated dose (MTD) to be determined in the Phase 1 part every 6 weeks in combination with 200 mg pembrolizumab every 3 weeks.	Drug: Radium-223 dichloride (Xofigo, BAY 88-8223); 55 kBq/kg, intravenous (IV) injection, every 6 weeks for up to 6 administrations; Drug: Pembrolizumab; 200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations
Active Comparator: Phase 2 Cohort 1: Pembrolizumab alone; Participants was planned to receive 200 mg pembrolizumab every 3 weeks.	Drug: Pembrolizumab; 200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations
Experimental: Phase 2 Cohort 2: Radium-223+Pembrolizumab; Participants was planned to receive radium-223 dichloride at the MTD to be determined in the Phase 1 part every 6 weeks in combination with 200 mg pembrolizumab every 3 weeks.	Drug: Radium-223 dichloride (Xofigo, BAY 88-8223); 55 kBq/kg, intravenous (IV) injection, every 6 weeks for up to 6 administrations; Drug: Pembrolizumab; 200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events in Phase 1	A treatment-emergent adverse event (TEAE) was any untoward medical occurrence in a participant, whether or not related to the treatment, arising or worsening after start of study treatment administration until the end of treatment visit (EoT visit, i.e. 30 [+7] days after last dose of study treatment). Severities of the TEAEs are summarized overall and by the maximum grade experienced by the participants for any TEAEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0.	Up to 218 days
Number of Participants With Treatment-emergent Serious Adverse Events in Phase 1	A treatment-emergent serious adverse event (TESAE) was any untoward medical occurrence that resulting in death, initial or prolonged inpatient hospitalization, life-threatening, persistent disability/incapacity, congenital anomaly/birth defect, another medical important serious event as judged by the investigator arising or worsening after start of study treatment administration until 90 days after the cessation of study treatment for serious AE (regardless of causality) or until the end of treatment visit (EoT visit, i.e. 30 [+7] days after last dose of study treatment) visit if the participant initiated new anti-cancer therapy, whichever was earlier.	Up to 278 days
Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1	Any of following toxicities (exceptions as in protocol) during DLT window was considered a DLT if assessed by investigator to be possibly, probably or definitely related to study treatment: 1.Grade 4 non-hematologic toxicity. 2.Grade 4 hematologic toxicity ≥7 days. 3.Any non-hematologic AE (excl. lab) ≥Grade 3. 4.Any Grade 3 non-hematologic lab value if clinically significant medical intervention required, or the abnormality led to hospitalization, or the abnormality persisted for >1 week. 5.Grade 3 abnormality in AST, ALT, or bilirubin without liver metastases at screening; The abnormality results in a Drug-induced Liver Injury. 6.Febrile neutropenia Grade 3 or 4. 7.Prolonged delay (>2 weeks) in initiating Cycle 2 of pembrolizumab due to treatment-related toxicity 8.Any treatment-related toxicity that caused the participant to discontinue treatment during Cycle 1 or 2. 9.Missing >25% of pembrolizumab doses as a result of drug-related AE(s) during the first cycle. 10.Grade 5 toxicity.	Within 6 weeks after the first administration of pembrolizumab
Objective Response Rate (ORR) Per RECIST v1.1 in Phase 2	ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) during the course of the study. It was evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1). Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions.	0 day as Phase 2 never started due to the early termination of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Categorized by Best Tumor Responses Per RECIST v1.1 in Phase 1	The tumor responses were evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1).	Up to 188 days
Objective Response Rate (ORR) Per RECIST v1.1 in Phase 1	ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) during the course of the study. It was evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1). Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Number of participants with best overall response of CR or PR before early termination of the study is reported in the table below while percentage of participants is auto-calculated by ClinicalTrials.gov database.	Up to 188 days
Duration of Response (DoR) Per RECIST v1.1 in Phase 1	DoR was 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. It was evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1). Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions.	Up to 188 days
Disease Control Rate (DCR) Per RECIST v1.1 in Phase 1	DCR was defined as the percentage of participants with CR or PR, or SD for at least 6 weeks during the course of the study. It was evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1). Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Stable Disease (SD): Steady state of disease. Number of participants with best overall response of CR or PR or SD is reported below while percentage of participants is auto-calculated by ClinicalTrials.gov database.	Up to 188 days
Duration of Response (DoR) Per RECIST v1.1 in Phase 2	DoR was 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. It was evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1). Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions.	0 day as Phase 2 never started due to the early termination of the study
Disease Control Rate (DCR) Per RECIST v1.1 in Phase 2	DCR was defined as the percentage of participants with CR or PR, or SD for at least 6 weeks during the course of the study. It was evaluated per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST V1.1). Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Stable Disease (SD): Steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non target lesions and no appearance of new lesions.	0 day as Phase 2 never started due to the early termination of the study
Progression Free Survival (PFS) Per RECIST v1.1 in Phase 2	Progression free survival (PFS) was defined as the time from start of any study treatment to the date of earliest radiological progression per RECIST 1.1 or death due to any cause, whichever occurs first. Participants who were alive and without progression at the time of database cut-off would be censored at the date of the last evaluable tumor assessment. RECIST: Response Evaluation Criteria in Solid Tumors	0 day as Phase 2 never started due to the early termination of the study
Overall Survival (OS) in Phase 2	Overall survival (OS) was defined as the time from start of any study treatment to the date of death due to any cause. Participants who were alive at the time of database cut-off would be censored at the last date known to be alive or the database cut-off date, whichever occurs first.	0 day as Phase 2 never started due to the early termination of the study
Number of Participants With Treatment-emergent Adverse Events in Phase 2	An treatment-emergent adverse event (TEAE) was any untoward medical occurrence in a participant, whether or not related to the treatment, arising or worsening after start of study treatment administration until the end of treatment visit (EoT visit, i.e. 30 [+7] days after last dose of study treatment). Severities of the TEAEs are summarized overall and by the maximum grade experienced by the participants for any TEAEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0.	0 day as Phase 2 never started due to the early termination of the study
Number of Participants With Treatment-emergent Serious Adverse Events in Phase 2	A treatment-emergent serious adverse event (TESAE) was any untoward medical occurrence that resulting in death, initial or prolonged inpatient hospitalization, life-threatening, persistent disability/incapacity, congenital anomaly/birth defect, another medical important serious event as judged by the investigator arising or worsening after start of study treatment administration until 90 days after the cessation of study treatment for serious AE (regardless of causality) or until the end of treatment visit (EoT visit, i.e. 30 [+7] days after last dose of study treatment) visit if the participant initiated new anti-cancer therapy, whichever was earlier.	0 day as Phase 2 never started due to the early termination of the study

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2020
• Primary Completion (Actual): April 14, 2021
• Study Completion (Actual): January 30, 2023

Study Registration Dates

• First Submitted: June 21, 2019
• First Submitted That Met QC Criteria: June 21, 2019
• First Posted (Actual): June 24, 2019

Study Record Updates

• Last Update Posted (Actual): October 10, 2024
• Last Update Submitted That Met QC Criteria: July 22, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; Radium Ra 223 dichloride
• Other Study ID Numbers: 19781; 2018-003704-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No