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

• ClinicalTrials.gov Identifier: NCT03996473
• Recruitment Status: Active, not recruiting
• First Posted: June 24, 2019
• Last Update Posted: May 12, 2021
• Sponsor: Bayer
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Bayer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Radium-223 dichloride (Xofigo, BAY 88-8223); Drug: Pembrolizumab	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 164 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 6, 2020
• Actual Primary Completion Date: April 14, 2021
• Estimated Study Completion Date: January 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of participants with adverse events (AEs) in Phase 1 [ Time Frame: Until 30 days after the last dose of the study intervention (up to 3 years) ]
2. Number of participants with dose limiting toxicities (DLTs) in Phase 1 [ Time Frame: Up to 6 weeks ]
3. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in Phase 2 [ Time Frame: Up to 36 weeks ]
   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.

Secondary Outcome Measures :

1. ORR per RECIST v1.1 in Phase 1 [ Time Frame: Up to 5 years ]
2. Duration of response (DoR) per RECIST v1.1 in Phase 1 [ Time Frame: Up to 5 years ]
   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.
3. Disease control rate (DCR) per RECIST v1.1 in Phase 1 [ Time Frame: Up to 5 years ]
   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.
4. DoR per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
5. DCR per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
6. Progression free survival (PFS) per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
   PFS is defined as the time period until the date of radiological progression or death whichever occurs first.
7. Overall survival (OS) in Phase 2 [ Time Frame: Up to 5 years ]
   OS is defined as the time period until the death due to any cause.
8. Number of participants with AE in Phase 2 [ Time Frame: Until 30 days after the last dose of the study intervention (up to 5 years) ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Ccare San Marcos Cancer Center & Urology

San Marcos, California, United States, 92069

Belgium

UZ Gent

Gent, Belgium, 9000

Netherlands

Nederlands Kanker Instituut

Amsterdam, Netherlands, 1066 CX

Spain

Ciutat Sanitària i Universitaria de la Vall d'Hebron

Barcelona, Spain, 08035

Hospital Clínic i Provincial de Barcelona

Barcelona, Spain, 08036

Hospital Universitario 12 de Octubre

Madrid, Spain, 28041

Sponsors and Collaborators

Bayer

Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT03996473
• Other Study ID Numbers: 19781; 2018-003704-39 ( EudraCT Number )
• First Posted: June 24, 2019
• Last Update Posted: May 12, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Plan Description

Availability of this study's data will 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.clinicalstudydatarequest.com 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 Study sponsors section of the portal.

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

Keywords provided by Bayer:

NSCLC

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Pembrolizumab; Radium Ra 223 dichloride; Antineoplastic Agents, Immunological; Antineoplastic Agents