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出境医 / 临床实验 / 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 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 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
Layout table for study information
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
Layout table for eligibility information
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
Layout table for location information
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.
Tracking Information
First Submitted Date  ICMJE June 21, 2019
First Posted Date  ICMJE June 24, 2019
Last Update Posted Date June 10, 2021
Actual Study Start Date  ICMJE March 6, 2020
Actual Primary Completion Date April 14, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 7, 2020)
  • 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) ]
  • Number of participants with dose limiting toxicities (DLTs) in Phase 1 [ Time Frame: Up to 6 weeks ]
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 21, 2019)
  • 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 4 years) ]
  • Number of participants with dose limiting toxicities (DLTs) in Phase 1 [ Time Frame: Up to 6 weeks ]
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2020)
  • ORR per RECIST v1.1 in Phase 1 [ Time Frame: Up to 5 years ]
  • 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.
  • 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.
  • DoR per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
  • DCR per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
  • 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.
  • 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.
  • 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) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 21, 2019)
  • ORR per RECIST v1.1 in Phase 1 [ Time Frame: Up to 5 years ]
  • ORR per iRECIST in Phase 1 [ Time Frame: Up to 5 years ]
  • 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.
  • DOR per iRECIST in Phase 1 [ Time Frame: Up to 5 years ]
  • 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.
  • DCR per iRECIST in Phase 1 [ Time Frame: Up to 5 years ]
  • ORR per iRECIST in Phase 2 [ Time Frame: Up to 5 years ]
  • DoR per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
  • DOR per iRECIST in Phase 2 [ Time Frame: Up to 5 years ]
  • DCR per RECIST v1.1 in Phase 2 [ Time Frame: Up to 5 years ]
  • DCR per iRECIST in Phase 2 [ Time Frame: Up to 5 years ]
  • 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.
  • PFS per iRECIST in Phase 2 [ Time Frame: Up to 5 years ]
  • 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.
  • 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) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Non-Small-Cell Lung
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Phase 1: Radium-223+Pembrolizumab
    Participants will receive radium-223 dichloride every 6 weeks in combination with pembrolizumab every 3 weeks
    Interventions:
    • Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)
    • Drug: Pembrolizumab
  • Experimental: Phase 2 Cohort 1: Radium-223+Pembrolizumab
    Participants will receive radium-223 dichloride every 6 weeks in combination with pembrolizumab every 3 weeks
    Interventions:
    • Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)
    • Drug: Pembrolizumab
  • Active Comparator: Phase 2 Cohort 1: Pembrolizumab alone
    Participants will receive pembrolizumab every 3 weeks
    Intervention: Drug: Pembrolizumab
  • Experimental: Phase 2 Cohort 2: Radium-223+Pembrolizumab
    Participants will receive radium-223 dichloride every 6 weeks in combination with pembrolizumab every 3 weeks
    Interventions:
    • Drug: Radium-223 dichloride (Xofigo, BAY 88-8223)
    • Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 21, 2019) 		164
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2023
Actual Primary Completion Date April 14, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Netherlands,   Spain,   United States
Removed Location Countries Germany,   Israel,   Italy,   Japan,   Poland,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT03996473
Other Study ID Numbers  ICMJE 19781
2018-003704-39 ( EudraCT Number )
Has Data Monitoring Committee Yes
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  ICMJE
Plan to Share IPD: No
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.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.
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE Not Provided
PRS Account Bayer
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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