Clinical Trial Results:
Two-arm randomized phase II trial to assess the feasibility and efficacy of a treatment with Durvalumab a PDL1-Inhibitor plus Tremelimumab a CTLA-4- Inhibitor in combination with radiotherapy and a treatment with Durvalumab in combination with radiotherapy as first-line therapy for patients with non-resectable locally advanced HPV negative HNSCC- A COMPARISON WITH A HISTORICAL CONTROL GROUP-DuTRe-raD.
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Summary
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EudraCT number |
2016-003175-22 |
Trial protocol |
DE |
Global end of trial date |
14 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Jan 2024
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First version publication date |
27 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 |
CCCC-H&N-IRT-1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03624231 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Charité- Universitätsmedizin Berlin
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Sponsor organisation address |
Charitéplatz 1, Berlin, Germany, 10117
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Public contact |
PD Dr. Konrad Klinghammer, Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, Cambus Benjamin Franklin, +49 030 450513525, konrad.klinghammer@charite.de
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Scientific contact |
Prof . Dr. Ulrich Keilholz, Head of CCCC, Charité Comprehensive Cancer Center CCCC, +49 030 450564621, ulrich.keilholz@charite.de
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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 |
27 Jun 2022
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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 |
14 Jul 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 |
The primary objective is to explore the feasibility and efficacy in terms of treatment discontinuation due to toxicity and in terms of 1-year progression free survival of a PDL1-Inhibitor plus a CTLA-4 Inhibitor in combination with radiotherapy vs a PDL1-Inhibitor in combination with radiotherapy as first-line therapy for patients with non-resectable locally advanced HNSCC in the poor prognostic subgroup.
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Protection of trial subjects |
Adverse events and serious adverse events were recorded from time of signature of informed consent, throughout the treatment period and including the follow-up period (90 days after the last dose of Durvalumab). Safety was assessed on a schedule based on the date of the first dose: Laboratory assessments (Coagulation parameters, pregnancy test, thyroid stimulating hormone, Hepatitis A, B and C virus antibodies, HIV antibodies, hematology tests, clinical chemistry tests, urinalysis test) was performed within 72 h before treatment application.
As the IMP has possible human teratogenicity/fetotoxicity in early pregnancy, pregnancy tests were performed in women of childbearing potential (WOCBP) every 8 weeks. Additionally, the investigators assessed antitumor activity based on radiological assessments and clinical evaluation of patients using modified RECIST v1.1 at baseline and during therapy every 8 weeks. For patients who achieved disease control following 12 months of treatment, or who discontinued the treatment due to toxicity, tumor assessments were performed every 12 weeks relative to the date of first infusion thereafter until confirmed PD by RECIST 1.1 by investigational site review.
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Background therapy |
DURTRERAD is a randomized phase II study evaluating feasibility and efficacy of durvalumab (anti-PD-L1) vs. durvalumab and tremelimumab (anti-CTLA-4) in combination with radiotherapy as primary treatment for locally advanced HPV negative HNSCC. (NCT03624231). Concurrent chemo-RT with a platinum-based regimen is considered the standard treatment, although efficacy and long-term toxicity are not satisfactory. Combining immunotherapy with RT might result in improved efficacy with limited long-term toxicity. Methods: The phase II study planned to enroll 120 pts, 60 pts (1:1) in each treatment arm. Treatment with DT (1500mg/75 mg, arm DT), or D (1500mg, arm D) both in combination with RT (70Gy) was considered to be feasible if less than 10% of the patients treated will discontinue treatment due to on-treatment toxicities. A first interim analysis for feasibility and efficacy was planned after randomisation of 20 patients. Results: So far 23 patients have been screened, 16 patients have been randomised and started their allocated treatment, 10 in arm D and 6 in arm DT. Of 10 patients in arm D 1 patient stopped infusional treatment due to immune related toxicity. Out of 6 patients in the DT arm, however, 5 patients stopped treatment due to treatment related AEs, 2 pts due to immune related toxicity with one Grade 5 AE. Three patients stopped due to non-immune related AE. The grade 5 AE prompted the interim analysis, which revealed non-feasibility as well as safety-issues of the DT+radiotherapy combination. As a result, the DT arm was prematurely terminated. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Oct 2018
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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 |
3 Months | ||
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 |
Germany: 18
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Worldwide total number of subjects |
18
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EEA total number of subjects |
18
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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) |
9
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From 65 to 84 years |
9
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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 3 study centers in Germany, between Date of first enrollment: 23/10/2018 and The last patient on the trial completed maintenance treatment on 01.10.2021. Date last patient last visit: 24/06/2022 | |||||||||
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Pre-assignment
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Screening details |
26 patients with Non-resectable locally advanced HPV negative HNSCC were screened, 8 screening failures. | |||||||||
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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 |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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DT + R | |||||||||
Arm description |
combination arm with Durvalumab and Tremelimumab and radiotherapy | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Durvalumab
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Investigational medicinal product code |
CAS-Code 1428935-60
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Other name |
MEDI4736, Imfinzi
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Solution for infusion
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Dosage and administration details |
Patients in arm will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy.
Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1).
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Investigational medicinal product name |
Tremelimumab
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Investigational medicinal product code |
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Other name |
Imjudo
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Solution for infusion
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Dosage and administration details |
Patients in arm will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy.
Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1).
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Arm title
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D + R | |||||||||
Arm description |
Durvalumab and radiotherapy | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Durvalumab
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Investigational medicinal product code |
CAS-Code 1428935-60
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Other name |
MEDI4736, Imfinzi
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Solution for infusion
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Dosage and administration details |
Patients in arm will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy.
Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14.
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End points reporting groups
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Reporting group title |
DT + R
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Reporting group description |
combination arm with Durvalumab and Tremelimumab and radiotherapy | ||
Reporting group title |
D + R
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Reporting group description |
Durvalumab and radiotherapy | ||
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End point title |
progression-free survival (PFS) [1] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
teatment + 3 month follow up
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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: Based on a failure rate of 10 %, it was planned to include 60 subjects. The analysis was to be conducted when 54 subjects reached follow-up. However, only 18 subjects were included and analysed. No statistical analyses were carried out. |
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Attachments |
safety and efficacy results |
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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 |
during treatment an up to 1 year after treatment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.03
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Reporting groups
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Reporting group title |
DT+R arm and D+R arm
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 Jul 2016 |
update protocol Version 4.1 |
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10 Jan 2020 |
update protocol Version 5.2 |
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13 Aug 2020 |
Amendments to the test plan and investigator's brochure for testing substances MEDI 4736/MEDI 1123 |
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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. | |||
| Enrollment in the trial was slower than expected. After the occurrence of a (SUSAR) in DT+R arm, this arm was terminated as specified in the protocol. The assumption of reaching a 30% PFS rate on D+R arm was judged to be unrealistic. | |||
