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

NCT03996473 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 197812018-003704-39
• Study Type: interventional
• Target: 8
• Locations: 4 countries
• Sites: 6

Brief Summary

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.

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

NSCLC

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (10)

• Number of Participants Categorized by Best Tumor Responses Per RECIST v1.1 in Phase 1

  Up to 188 days

• Objective Response Rate (ORR) Per RECIST v1.1 in Phase 1

  Up to 188 days

• Duration of Response (DoR) Per RECIST v1.1 in Phase 1

  Up to 188 days

• Disease Control Rate (DCR) Per RECIST v1.1 in Phase 1

  Up to 188 days

• Duration of Response (DoR) Per RECIST v1.1 in Phase 2

  0 day as Phase 2 never started due to the early termination of the study

Study Arms (4)

Phase 1: Radium-223+Pembrolizumab

EXPERIMENTAL

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); Drug: Pembrolizumab

Phase 2 Cohort 1: Radium-223+Pembrolizumab

EXPERIMENTAL

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); Drug: Pembrolizumab

Phase 2 Cohort 1: Pembrolizumab alone

ACTIVE COMPARATOR

Participants was planned to receive 200 mg pembrolizumab every 3 weeks.

Drug: Pembrolizumab

Phase 2 Cohort 2: Radium-223+Pembrolizumab

EXPERIMENTAL

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); Drug: Pembrolizumab

Interventions

Radium-223 dichloride (Xofigo, BAY 88-8223) DRUG

55 kBq/kg, intravenous (IV) injection, every 6 weeks for up to 6 administrations

Phase 1: Radium-223+Pembrolizumab; Phase 2 Cohort 1: Radium-223+Pembrolizumab; Phase 2 Cohort 2: Radium-223+Pembrolizumab

Pembrolizumab DRUG

200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations

Phase 1: Radium-223+Pembrolizumab; Phase 2 Cohort 1: Pembrolizumab alone; Phase 2 Cohort 1: Radium-223+Pembrolizumab; Phase 2 Cohort 2: Radium-223+Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bayer: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (6)

Ccare San Marcos Cancer Center & Urology

San Marcos, California, 92069, United States

Location

UZ Gent

Ghent, 9000, Belgium

Location

Nederlands Kanker Instituut

Amsterdam, 1066 CX, Netherlands

Location

Ciutat Sanitaria i Universitaria de la Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Clínic i Provincial de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Related 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.

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

radium Ra 223 dichloride; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

The study was terminated early during the Phase 1 part of the study. This decision was based on strategic considerations also acknowledging the recruitment challenges for the first-line population. Due to the early termination, tumor responses were only listed, none of the efficacy outcome measures were actually analyzed.

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

(+) 1-888-8422937

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2019
• First Posted: June 24, 2019
• Study Start: March 6, 2020
• Primary Completion: April 14, 2021
• Study Completion: January 30, 2023
• Last Updated: October 10, 2024
• Results First Posted: October 10, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); ES (3); BE (1); NL (1)