Clinical Trial Results:
A Phase II Trial Testing Durvalumab Combined With Endocrine Therapy in Patients With ER+/Her2- Breast Cancer Eligible for Neoadjuvant Endocrine Therapy And Who Present CD8+ T Cell Infiltration After 4-6 Weeks Exposure to Immune-Attractant.
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Summary
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EudraCT number |
2016-000764-42 |
Trial protocol |
FR ES |
Global end of trial date |
28 Jul 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Mar 2022
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First version publication date |
01 Mar 2022
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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 |
UC-0140/1606
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02997995 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
UNICANCER
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Sponsor organisation address |
101 rue de Tolbiac, Paris, France, 75013
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Public contact |
Nourredine AIT-RAHMOUNE, UNICANCER, 33 171936704, n.ait-rahmoune@unicancer.fr
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Scientific contact |
Nourredine AIT-RAHMOUNE, UNICANCER, 33 171936704, n.ait-rahmoune@unicancer.fr
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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 |
21 Jan 2021
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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 |
28 Jul 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy of durvalumab combined with exemestane in patients with CD8+ T cells on pathological response at surgery after a lymphocyte attraction phase.
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Protection of trial subjects |
In order to ensure the protection of the rights, safety and well-being of trial subjects, this clinical trial was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws.
Furthermore, independent Ethics Committees in France, Sweden and Belgium reviewed and gave a favorable opinion to the study documents, including the initial protocol and all subsequent amendments, and all information and documents provided to subjects/patients.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Mar 2017
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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 |
1 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 |
Spain: 9
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Country: Number of subjects enrolled |
France: 52
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Worldwide total number of subjects |
61
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EEA total number of subjects |
61
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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) |
31
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From 65 to 84 years |
30
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85 years and over |
0
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Recruitment
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Recruitment details |
Multicentric, open-label phase II trial testing an aromatase inhibitor in combination with durvalumab in ≥18 years old men or post-menopausal women eligible to neoadjuvant endocrine therapy for T2-4 ER+/HER2- breast cancer with CD8+T cell infiltration (>10% CD8+T cells in the tumour). patient recruitment: 02-Mar-2017 to 10-Apr-2020. | ||||||||||
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Pre-assignment
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Screening details |
The study consisted of a screening phase of up to 30 days before treatment initiation to establish eligibility and document baseline measurements, a part 1 treatment phase (6-week), a part 2 treatment phase (28-day cycle; 6 months), a surgery and a long-term follow-up to monitor pathological complete response, CD8 infiltration, Ki67, and safety. | ||||||||||
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Pre-assignment period milestones
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Number of subjects started |
61 | ||||||||||
Intermediate milestone: Number of subjects |
Part 1: Chemo-attractant: 61
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Number of subjects completed |
24 | ||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
CD8+T cells infiltration lower than 10%: 31 | ||||||||||
Reason: Number of subjects |
Adverse event, non-fatal: 3 | ||||||||||
Reason: Number of subjects |
Protocol deviation: 3 | ||||||||||
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Period 1
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Period 1 title |
Part 2 : Immunotherapy (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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Tremelimumab | ||||||||||
Arm description |
Part 1 used an open label, adaptive trial design of testing 4 to 6 weeks treatment with the immune attractants Tremelimumab plus Exemestane to increase CD8+T cell infiltration in the tumor site. Patients with >10% CD8+T cells in the tumor biopsy (3 weeks after Tremelimumab initiation) moved to the part 2 (core of the trial) of the study These patients received 6 months Exemestane plus Durvalumab before undergoing surgery. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Durvalumab
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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 |
Durvalumab was administered, concomitant to Exemestane, as an IV infusion over approximately 60 minutes (±5 minutes) every 4 weeks.
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Investigational medicinal product name |
Tremelimumab
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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 |
Tremelimumab was administered, concomitant to Exemestane (Section 9.4.1.2.1), as single IV infusion over approximately 60 minutes (±5 minutes).
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Investigational medicinal product name |
Exemestane
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Exemestane was prescribed in the therapeutic indication of neoadjuvant therapy for hormone receptor positive disease in postmenopausal women. Thus, the posology was 25 mg/day per os (p.o.: oral) until the day prior surgery.
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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: Patients must have >10% CD8+T cell infiltration in the tumor site after Tremelimumab treatment (Part 1). 37 out of 61 patients treated with Tremelimumab were not included in part 2 of the study due to a CD8+T cells infiltration lower than 10% (n=31), adverse events (n=3), and non-compliance to treatment (n=3). Thus, only 24 patients were included in part 2. The Baseline period reported here correspond to the part 2. |
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Baseline characteristics reporting groups
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Reporting group title |
Part 2 : Immunotherapy
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Reporting group description |
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End points reporting groups
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Reporting group title |
Tremelimumab
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Reporting group description |
Part 1 used an open label, adaptive trial design of testing 4 to 6 weeks treatment with the immune attractants Tremelimumab plus Exemestane to increase CD8+T cell infiltration in the tumor site. Patients with >10% CD8+T cells in the tumor biopsy (3 weeks after Tremelimumab initiation) moved to the part 2 (core of the trial) of the study These patients received 6 months Exemestane plus Durvalumab before undergoing surgery. | ||
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End point title |
pathological Complete Response [1] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
At surgery (7.5 months after inclusion)
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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: The Simon’s optimal two-stage design was used for the part 2 of this study. In the first stage, if 2 or more pathological complete responses (pCR) were observed in 23 patients, the part 2 could move to stage 2, otherwise the study had to be stopped . Only 1 patient had pCR, thus the futility criterion was met and the study was stopped. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Changes in CD8+ T-cells infiltration over time | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 weeks from Tremelimumab treatment initiation
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| No statistical analyses for this end point | |||||||||
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End point title |
Changes un Ki67 expression over time | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 weeks from Tremelimumab treatment initiation
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| No statistical analyses for this end point | |||||||||
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End point title |
Measurements of Tumour Infiltrating Lymphocytes (TILs) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 weeks from Tremelimumab treatment initiation
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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 |
24 months from inclusion
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Tremelimumab
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Reporting group description |
Part 1 used an open label, adaptive trial design of testing 4 to 6 weeks treatment with the immune attractants Tremelimumab plus Exemestane to increase CD8+T cell infiltration in the tumor site. Patients with >10% CD8+T cells in the tumor biopsy (3 weeks after Tremelimumab initiation) moved to the part 2 (core of the trial) of the study These patients received 6 months Exemestane plus Durvalumab before undergoing surgery. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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09 Jan 2018 |
A non-inclusion criterion has been added to exclude patients with previous malignancy within 5 years before inclusion in the study. Indeed, 5 years without recurrence is generally accepted as the minimum time to declare a person in remission. Basal cell carcinoma, squamous cell carcinoma of the skin and cervical carcinoma in situ, for which the cure rates are 100%, are not concerned by this measure. |
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14 May 2019 |
* An inclusion criterion has been reworded to make it clear that men can participate in this study.
* To clarify the conditions for patient transition between the part 1 to part 2 of the study, the 3 inclusion criteria and 2 exclusion criteria related to patient safety which are to be reevaluated before inclusion in part 2 were specified in the study protocol.
* A non-inclusion criterion was modified to exclude from Part 2 any patient who has experienced an adverse event of an immunological nature in Part 1.
* Modification of the interim safety analysis section following the IDMC decision. The new version indicated that the inclusion of patients in the study was stopped on February 26th 2018 for the purpose of this analysis. On April 30th 2018, the IDMC decided that, according to the rules of the interim safety analysis, the study should continue. |
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02 Jul 2019 |
The inclusion criteria related to patient contraception has been modified in order to clarify the condition of contraception in men participating in the study |
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22 Jun 2020 |
The planned interim efficacy analysis was performed on 22 out of 24 patients included in the part 2 of the study. Results demonstrated that the study did not reach its primary objective thus, as planned in the protocol, the inclusion of new patients were definitively stopped |
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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 1 out of 4 cohorts of patients was tested in part 1 (immune attractant) of the study. Concerning adverse events the "Occurrences all number" was not reported, thus, the number of patients is noted in this field. | |||
