Clinical Trial Results:
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
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Summary
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EudraCT number |
2018-003704-39 |
Trial protocol |
ES BE NL DE GB |
Global end of trial date |
30 Jan 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Jan 2024
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First version publication date |
26 Jan 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
19781
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03996473 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Feb 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jan 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Phase 1: To assess the safety of the combination of radium-223 dichloride and pembrolizumab and to determine the recommended Phase 2 dose (RP2D). Phase 2: To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone)
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Mar 2020
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
2 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 1
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Netherlands: 1
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Country: Number of subjects enrolled |
Spain: 6
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Worldwide total number of subjects |
10
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EEA total number of subjects |
9
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
5
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at multiple centers in 4 countries between 06 March 2020 (first subject first visit) and 30 January 2023 (last subject last visit). | ||||||||||||
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Pre-assignment
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Screening details |
Overall, 10 subjects were screened. Of them, 2 subjects were screen failures. 8 subjects were assigned to study treatment, of which 7 received the study treatment and 1 subject never received the treatment in the Phase 1. | ||||||||||||
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Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Radium-223 Dichloride + Pembrolizumab | ||||||||||||
Arm description |
Participants received radium-223 dichloride at 55 kBq/kg every 6 weeks in combination with pembrolizumab every 3 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
200 mg, IV infusion, every 3 weeks for a maximum of up to 35 administrations
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Investigational medicinal product name |
Radium-223 Dichloride
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Investigational medicinal product code |
BAY88-8223
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
55 kBq/kg, intravenous (IV) injection, every 6 weeks for up to 6 administrations
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The study was terminated early during the Phase 1 part of the study. No subjects started in Phase 2 part of the study prior to study termination. |
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Baseline characteristics reporting groups
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Reporting group title |
Radium-223 Dichloride + Pembrolizumab
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Reporting group description |
Participants received radium-223 dichloride at 55 kBq/kg every 6 weeks in combination with pembrolizumab every 3 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Radium-223 Dichloride + Pembrolizumab
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Reporting group description |
Participants received radium-223 dichloride at 55 kBq/kg every 6 weeks in combination with pembrolizumab every 3 weeks. | ||
Subject analysis set title |
Safety analysis set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The SAF consisted of all subjects who received at least 1 administration of study treatment.
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Subject analysis set title |
Dose limiting toxicities (DLT) analysis set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
DLT analysis set included all the following participants: a. participants who experienced a DLT during the DLT observation window; b. participants who did not experience a DLT, and who were not dropouts. Dropouts were eligible participants who withdrew during the DLT observation window (within 6 weeks after the first administration of pembrolizumab) for reasons other than experiencing a DLT, and who did not complete both 1 dose of radium-223 dichloride and 2 cycles of pembrolizumab.
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Subject analysis set title |
Efficacy analysis set (EFF)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
EFF included all subjects who received at least 1 administration of planned dose of any study treatment In Phase 1.
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End point title |
Number of subjects with treatment-emergent adverse events in Phase 1 [1] | ||||||||||||||||
End point description |
A treatment-emergent adverse event (TEAE) was any untoward medical occurrence in a subject, 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 subjects for any TEAEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0.
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End point type |
Primary
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End point timeframe |
Up to 218 days
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial and due to the limited sample size, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed. |
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| Notes [2] - SAF |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Number of subjects with treatment-emergent serious adverse events in Phase 1 [3] | ||||||||
End point description |
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 subject initiated new anti-cancer therapy, whichever was earlier.
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End point type |
Primary
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End point timeframe |
Up to 278 days
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial and due to the limited sample size, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed. |
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| Notes [4] - SAF |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with dose limiting toxicities (DLTs) in Phase 1 [5] | ||||||||
End point description |
Any of following toxicities (exceptions as in protocol) during the 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 subject 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
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End point type |
Primary
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End point timeframe |
Within 6 weeks after the first administration of pembrolizumab
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial and due to the limited sample size, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed. |
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| Notes [6] - DLT analysis set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Objective response rate (ORR) per RECIST v1.1 in Phase 2 [7] | ||||||||
End point description |
ORR was defined as the percentage of subjects with best overall response of complete response (CR) or partial response (PR) during the course of the study. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Primary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the nature of this trial and due to the limited sample size, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed. |
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| Notes [8] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of participants categorized by best tumor responses per RECIST v1.1 in Phase 1 | ||||||||||||
End point description |
The RECIST v1.1 criteria were used for efficacy evaluation of response and disease control. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Secondary
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End point timeframe |
Up to 188 days
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| Notes [9] - EFF |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Objective response rate (ORR) per RECIST v1.1 in Phase 1 | ||||||||
End point description |
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. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Secondary
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End point timeframe |
Up to 188 days
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| Notes [10] - ORR wasn’t analyzed due to no responder reported before study termination among low number subjects |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of response (DoR) per RECIST v1.1 in Phase 1 | ||||||||
End point description |
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. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Secondary
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End point timeframe |
Up to 188 days
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| Notes [11] - DoR wasn’t analyzed due to no responder reported before study termination among low number subjects |
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| No statistical analyses for this end point | |||||||||
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End point title |
Disease control rate (DCR) per RECIST v1.1 in Phase 1 | ||||||||
End point description |
DCR was defined as the percentage of subjects with CR or PR, or SD for at least 6 weeks during the course of the study. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Secondary
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End point timeframe |
Up to 188 days
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| Notes [12] - DCR wasn't analyzed due to study termination and the low number of subjects |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of response (DoR) per RECIST v1.1 in Phase 2 | ||||||||
End point description |
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. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Secondary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [13] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||||
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End point title |
Disease control rate (DCR) per RECIST v1.1 in Phase 2 | ||||||||
End point description |
DCR was defined as the percentage of subjects with CR or PR, or SD for at least 6 weeks during the course of the study. RECIST: Response Evaluation Criteria in Solid Tumors
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End point type |
Secondary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [14] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression free survival (PFS) per RECIST v1.1 in Phase 2 | ||||||||
End point description |
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. Subjects 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
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End point type |
Secondary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [15] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall survival (OS) in Phase 2 | ||||||||
End point description |
Overall survival (OS) was defined as the time from start of any study treatment to the date of death due to any cause. Subjects 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.
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End point type |
Secondary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [16] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with treatment-emergent adverse events in Phase 2 | ||||||
End point description |
A treatment-emergent adverse event (TEAE) was any untoward medical occurrence in a subject, 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 subjects for any TEAEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0.
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End point type |
Secondary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [17] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of participants with treatment-emergent serious adverse events in Phase 2 | ||||||
End point description |
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 subject initiated new anti-cancer therapy, whichever was earlier.
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End point type |
Secondary
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End point timeframe |
0 day as Phase 2 never started due to the early termination of the study
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| Notes [18] - No subject started in Phase 2 part of the study prior to study termination |
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of study treatment to 90 days after cessation of study treatment or 30 days after last dose of study treatment (EoT visit) if subject started new anti-cancer therapy (whichever was earlier) for serious TEAEs; or until EoT visit for other TEAEs
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Adverse event reporting additional description |
Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the entire study before the last contact (i.e. from signing ICF until the end of follow-up)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Radium-223 + Pembrolizumab
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Reporting group description |
Subjects received radium-223 dichloride every 6 weeks for up to 6 administrations in combination with pembrolizumab every 3 weeks for up to 35 cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Oct 2019 |
Protocol amendment 1 was prepared to clarify and strengthen guidance on tumor assessment, eligibility criteria, toxicity management and DLT criteria. |
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18 Sep 2020 |
Protocol amendment 2 was mainly prepared to address the following points: clarification on eligibility criteria, concomitant therapy and dose modification rules, tumor assessment per iRECIST 1.1 moved from secondary to exploratory endpoints, clarification on statistical assumptions and planned analyses, provision of additional guidance to the participating sites, and additional background information on study rationale. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The study was terminated early during the Phase 1 part of the study. Due to the early termination, tumor responses were only listed, none of the efficacy outcome measures were actually analyzed. | |||
