Clinical Trial Results:
A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of Avelumab in Combination with Bempegaldesleukin (NKTR-214) with or without Talazoparib or Enzalutamide in Participants with Locally Advanced or Metastatic Solid Tumors
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Summary
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EudraCT number |
2019-001358-24 |
Trial protocol |
PL IT ES BE |
Global end of trial date |
29 Sep 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Sep 2021
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First version publication date |
08 Sep 2021
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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 |
B9991040
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04052204 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 East 42nd Street, New York, NY, United States, 10017-5755
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., Pfizer Inc., +1 8007181021, ClinicalTrails.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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 |
22 Jan 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
29 Sep 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Sep 2020
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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 |
The primary object of this trial was to assess the dose-limiting toxicity (DLT) rate of avelumab in combination with bempegaldesleukin (NKTR-214) (Combination A) to determine the recommended Phase 2 dose (RP2D) for the combinations.
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Protection of trial subjects |
This study was conducted in compliance with the ethical principles originated or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All local regulatory requirements were followed.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Dec 2019
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
2 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Belgium: 1
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Country: Number of subjects enrolled |
Poland: 1
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Country: Number of subjects enrolled |
Spain: 1
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Worldwide total number of subjects |
3
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EEA total number of subjects |
3
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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) |
2
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||
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Pre-assignment
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Screening details |
4 subjects screened for this study, 1 of the 4 subjects was a screen failure, 3 subjects were enrolled and received study treatment in Combination A. | ||||||||||||||
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Period 1
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Period 1 title |
Period 1 (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Avelumab + Bempegaldesleukin (NKTR-214) (Combination A) | ||||||||||||||
Arm description |
NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25). | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Bempegaldesleukin
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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 |
Each subject’s NKTR-214 dose was determined based on the subject’s weight in kilograms on Day 1 of each cycle. NKTR-214 was administered prior to avelumab. NKTR-214 was administered IV over 30 (± 5) minutes every 2 weeks (+/- 2 days).
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Investigational medicinal product name |
Avelumab
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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 |
Avelumab was administered at 800 mg as a 1-hour (-10/+20 minutes) IV infusion starting after the NKTR-214 and talazoparib or enzalutamide (where applicable) was administered, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle.
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Baseline characteristics reporting groups
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Reporting group title |
Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
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Reporting group description |
NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Avelumab + Bempegaldesleukin (NKTR-214) (Combination A)
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Reporting group description |
NKTR-214 was administered prior to avelumab. NKTR-214 0.006 mg/kg was administered intravenously (IV) over 30 minutes every 2 weeks (Q2W). Avelumab 800 mg as a 1-hour IV infusion was administered after the NKTR-214 Q2W, at the investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle. Within the 2-day window, avelumab and NKTR-214 were administered on the same day. Dose reduction of NKTR-214 to 0.003 mg/kg Q2W was triggered if higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 0.25). | ||
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End point title |
Number of Subjects with Dose Limiting Toxicities (DLT) [1] | ||||||||
End point description |
DLTs were graded according to NCI- CTCAE version 4.03 and coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) as event category and MedDRA primary system organ class (SOC) body term as Body System category. The DLT-evaluable analysis set was a subset of the safety analysis set and included all enrolled subjects in Phase 1b who received at least one dose of the combination treatment and either experienced DLT during the first cycle (28 days) of treatment, or completed the DLT observation period for the first cycle of treatment without a DLT.
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End point type |
Primary
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End point timeframe |
Cycle 1 of the treatment period (28 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: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response (DR) | ||||||||
End point description |
DR was defined, for subjects with a confirmed Objective Response (OR), as the time from the first documentation of OR to the date of first documentation of progressive disease (PD) or death due to any cause. The documentation of PD was defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If a subject had not had an event (PD or death), DR was censored at the date of last adequate tumor assessment. All subjects treated in combination A who achieved an OR were analyzed.
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End point type |
Secondary
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End point timeframe |
Approximately 8 months (246 days).
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| Notes [2] - As there were no ORs in the study, no participant met the definition of analysis population. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Tumor Response (TTR) | ||||||||
End point description |
TTR was defined, for subjects with OR, as the time from the date of first dose of study treatment to the first documentation of objective response (Complete Response or Partial Response) which was subsequently confirmed. All subjects treated in combination A who achieved an OR were analyzed. 99999 indicates that TTR was not analyzed due to no objective responses in the study.
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End point type |
Secondary
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End point timeframe |
Approximately 8 months (246 days).
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| Notes [3] - As there were no ORs in the study, no participant met the definition of analysis population. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression-Free Survival (PFS) | ||||||||
End point description |
Progression-Free Survival (PFS): the time from the date of first dose of study treatment to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PFS data were censored on the date of the last adequate tumor assessment for subjects who did not have an event (PD or death), for subjects who started new anti-cancer therapy prior to an event, or for subjects with an event after two or more missing tumor assessments. Subjects who did not have an adequate baseline tumor assessment or who did not have any adequate post-baseline tumor assessments were censored on the date of first dose of study treatment unless death occurred on or before the time of the second planned tumor assessment, in which case death was considered an event. Two subjects had best overall response of PD and 1 was not evaluable due to early death. One subject died on days 18, another died on day 77. 99999 indicates no summaries of PFS endpoints, because N<= 3.
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End point type |
Secondary
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End point timeframe |
Approximately 8 months (246 days).
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
OS was defined as the time from the first dose of study treatment to the date of death due to any cause. Patients last known to be alive were censored at date of last contact. All subjected treated in combination A were analyzed. one subject died 18 after the first dose of treatment, 1 patient did 77 days after first dose of treatment. the 3 subject was censored 191 days after first dose (first dose date 23Mar2020, end of study 29Sep2020). 99999 indicates that there were no summaries of OS endpoints, because N<= 3.
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End point type |
Secondary
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End point timeframe |
Approximately 8 months (246 days)
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic (PK) parameters - Cmax and Ctrough for Avelumab and NKTR-214 | ||||||||
End point description |
Cmax was defined as the maximum observed plasma concentration at the end of infusion. Ctrough was defined as the predose concentration at the end of dosing interval. The PK parameter analysis set was a subset of the safety analysis set and included subjects who had at least one of the PK parameters of interest for avelumab, NKTR-214, IL-2, talazoparib, enzalutamide, or N-desmethyl-enzalutamide. 99999 indicates that there were no summaries and interpretations of PK results available, because N<=3 in the PK analysis set.
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End point type |
Secondary
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End point timeframe |
Blood samples were collected on Day 1 and Day 15 in Cycle 1 and Cycle 2 for avelumab. Blood samples were collected on Day 1, Day 3, Day 4 and Day 8 in Cycle 1, Day1 and Day 8 in Cycle 2 for NKTR-214.
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects with Positive Anti-Drug Antibody (ADA) Results | ||||||
End point description |
ADA against avelumab and NKTR-214 in serum samples was determined and reported separately for ADA never-positive, ADA ever-positive, baseline ADA positive, treatment-boosted ADA, treatment-induced ADA, transient ADA response, Persistent ADA response. For all subjects, blood for ADA samples will be drawn from the contralateral arm of the avelumab and NKTR-214 infusion. The immunogenicity analysis set was a subset of the safety analysis set and included subjects who had at least one ADA/nAb sample collected for avelumab, NKTR-214, or IL-2. 99999 indicates that ADA results were not analyzed for this study due to study termination.
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End point type |
Secondary
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End point timeframe |
Day 1 of Cycle 1, Cycle 2 and end of treatment (EOT).
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects with Positive Neutralizing Antibody (nAb) Results | ||||||
End point description |
Samples positive for ADA were analyzed for nAb, nAb in serum samples was determined and reported separately for nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response. The immunogenicity analysis set was a subset of the safety analysis set and included subjects who had at least one ADA/nAb sample collected for avelumab, NKTR-214, or IL-2. 99999 indicates that nAb results were not analyzed for this study due to study termination.
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End point type |
Secondary
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End point timeframe |
Day 1 of Cycle 1, Cycle 2, and EOT.
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| No statistical analyses for this end point | |||||||
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End point title |
PD-L1 Expression Level in Baseline and On-treatment Tumor Tissue | ||||||
End point description |
PD-L1 expression level in baseline tumor tissue, and in on-treatment tumor tissue was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and/or inflammatory cells in regions of interest. PD-L1 expression level in baseline tumor tissue and in on-treatment tumor tissue were under pathological analyses, assisted by image analysis. Subjects were classified as positive or negative according to scoring algorithms and cut-offs established from internal or external sources. The biomarker analysis set for biomarkers that were only measured at screening was a subset of the safety analysis set and included subjects who had at least one baseline biomarker assessment. 99999 indicates that no biomarker data (PD-L1) were analyzed for this study due to early study termination.
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End point type |
Secondary
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End point timeframe |
On-treatment biopsy was required to be collected on Cycle 1 between Days 9 and 14 for subjects in Combination A.
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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(TEAEs), Serious TEAEs, TEAEs Leading to Death and Infusion-Related Reactions (IRRs) During On-treatment Period | ||||||||||||||||||||||||
End point description |
Adverse events (AEs) were any untoward medical occurrences in a subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period, which was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment). A Serious Adverse Event (SAE) was defined as any untoward medical occurrence that, at any dose: a. Results in death, b. Was life-threatening, c. Required inpatient hospitalization or prolongation of existing hospitalization, d. Resulted in persistent disability/incapacity, e. Was a congenital anomaly/birth defect. Causality to study treatment was determined by the investigator. The safety analysis set included all subjects who received at least one dose of study drug. "Treatment-Related" is abbreviated as "TR" “All-Causality” is abbreviated as “AC”
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End point type |
Secondary
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End point timeframe |
Approximately 6 months (190 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Number of Subjects with Laboratory Abnormalities | ||||||||
End point description |
Liver Function Tests of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBILI) were used to assess possible drug induced liver toxicity. The number of subjects with at least one of the following laboratory results were summarized below: 1. (ALT ≥3 × ULN or AST ≥3 × ULN) post-baseline. 2. TBILI ≥2 × ULN post-baseline. 3. (ALP ≤2 × ULN or missing) post-baseline.
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End point type |
Secondary
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End point timeframe |
Day 1, Day 15 of each treatment cycle
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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 the subject provided informed consent to a minimum of 90 calendar days after the last administration of the investigational product.
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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 |
23.0
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Reporting groups
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Reporting group title |
Dose-Finding for Combination A
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Reporting group description |
Subjects were administrated 800mg avelumab plus 0.006mg/kg bempegaldesleukin(NKTR-214) intravenous(IV) every 2 weeks (Q2W) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Jun 2019 |
This amendment is to expand the Dose Limiting Toxicity(DLT) criteria following the feedback received from the FDA during the IND application review. |
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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. | |||
| Only Phase 1b of Combination A was conducted as company terminated this study on 21 May 2020. Termination was not due to a regulatory request or new emerging safety signals. Combination B, C and Phase 2 expansion for Combination A were not tested. | |||
