Clinical Trial Results:
A phase II study to evaluate safety and efficacy of combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma
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Summary
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EudraCT number |
2010-019033-98 |
Trial protocol |
DE |
Global end of trial date |
23 Jun 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Oct 2021
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First version publication date |
29 Oct 2021
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Other versions |
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Summary report(s) |
Adverse Events Information |
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 |
BMS-TUE-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01480323 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Hospital Tuebingen
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Sponsor organisation address |
Geissweg 3, Tuebingen, Germany, 72076
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Public contact |
PD Dr. med. Benjamin Weide, University Hospital Tuebingen, +49 7071 / 2985748, benjamin.weide@med.uni-tuebingen.de
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Scientific contact |
Prof. Dr. Michael Bamberg , University Hospital Tuebingen, +49 7071 / 298216, michael.bamberg@med.uni-tuebingen.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 |
24 May 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Jun 2015
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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 |
The main purpose of the trial was to assess the efficacy of the combined treatment with ipilimumab and intratumoral IL-2 based on the Disease Control Rate according to immune-related Response Criteria (irDCR) at week 12
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Protection of trial subjects |
Before the beginning of the study, approval of the responsible Independent Ethics Committee (IEC) was obtained. The responsible IEC of the coordinating investigator was the ethics committee of medical faculty of the University of Tuebingen. The study was approved on 27.10.2011. Protocol Amendment 1 was approved on 08.04.2013 by the responsible IEC. The regulatory basis of the conduct of this study consisted of the Declaration of Helsinki (in its current version), the AMG (German Medicinal Products Act), in particular Sections 40-42 in the current versions, and the principles of the proper conduct of clinical trials (ICH GCP). In accordance with the AMG, the sponsor had taken out insurance for all subjects who gave consent to participation in the clinical trial. The Investigator provided adequate information to the subject prior to subject signing the informed consent. The Institute provided an information sheet to the subjects and prepared it in accordance with the Note for Guidance on Good Clinical Practice (ICH, Topic E6, 1995) for the purpose of obtaining informed consent. In addition to this written information, the Investigator informed the subject verbally.
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Background therapy |
Concomitant systemic or local anti-cancer medications or treatments were prohibited in this study while receiving study treatment. Furthermore the following therapies during the study were prohibited: · Any non-study anti-cancer agent (investigational or non-investigational) · Any other investigational agents · Any other CTLA-4 inhibitors or agonists · CD137 agonists · Immunosuppressive agents · Chronic systemic corticosteroids · Any non-oncology vaccine therapies used for the prevention of infectious diseases (for up to 30 days prior to or after any dose of study drug). | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
16 Feb 2012
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Long term follow-up planned |
No
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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: 15
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Worldwide total number of subjects |
15
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EEA total number of subjects |
15
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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) |
15
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 15 patients from 1 site (Tuebingen Center for Dermato-Oncology, Investigator: PD Dr. med. Benjamin Weide) were enrolled from February 2012 to July 2014. | ||||||||||||||
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Pre-assignment
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Screening details |
In part 1 of this study 15 patients were enrolled from 1 site. 14 of 15 patients met all inclusion criteria and did not meet one of the exclusion criteria. All 15 patients were analysed for safety and efficacy evaluations. Due to the results of the second interim analysis no patients were enrolled in part 2 of the study. | ||||||||||||||
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Period 1
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Period 1 title |
Ipilimumab with intratumoral IL-2 (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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Treatment arm | ||||||||||||||
Arm description |
The treatment arm consisted of ipilimumab infusions (3mg/kg) every 3 weeks (days 2, 23, 44,65) for a total of four doses in combination with intralesional IL-2 at a dosage of 9 MIU distributed between all injected metastases proportionally to the respective lesion size at treatment days 1,4, 8, 11, 15, 18, 22 and 25. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
ipilimumab
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Investigational medicinal product code |
BMS-734016
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Other name |
Yervoy
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Pharmaceutical forms |
Concentrate and solvent for solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Each patient should have received ipilimumab at days 2, 23, 44 and 65 of the induction phase at a dosage of 3 mg/kg as an infusion. Infusions were given over 90 minutes (not bolus or IV push)
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Investigational medicinal product name |
IL-2
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Investigational medicinal product code |
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Other name |
Proleukin, Aldesleukin
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Pharmaceutical forms |
Injection
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Routes of administration |
Intralesional use
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Dosage and administration details |
Proleukin® S administration at a dosage of 9 MIU was planned at days 1, 4, 8, 11, 15, 18, 22 and 25 by intratumoral injections. The total daily dose was distributed between all selected soft-tissue metastases up to a maximum of 5. The total daily dose of 9 MIU IL-2 was distributed proportionally according to lesion sizes. Injections should have been guided by sonography for deep soft tissue metastases to ensure the intratumoral route of application
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Baseline characteristics reporting groups
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Reporting group title |
Ipilimumab with intratumoral IL-2
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Treatment arm
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Reporting group description |
The treatment arm consisted of ipilimumab infusions (3mg/kg) every 3 weeks (days 2, 23, 44,65) for a total of four doses in combination with intralesional IL-2 at a dosage of 9 MIU distributed between all injected metastases proportionally to the respective lesion size at treatment days 1,4, 8, 11, 15, 18, 22 and 25. | ||
Subject analysis set title |
Treatment arm
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Ipilimumab + IL-2
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End point title |
Disease Control Rate according to immune-related Response Criteria (irDCR) at week 12 [1] | |||||||||
End point description |
The primary endpoint of this study was the Disease Control rate according to immune-related Response Criteria (irDCR) at week 12. irDCR at week 12 represents the sum of patients with an
overall response (irCR or irPR or irSD) divided by the total number of patients, who were evaluable for efficacy. According to the definition of the evaluable set (see section 8.1) 15 patients were evaluable for the primary endpoint. 3 of the 15 patients (20.0%) showed irSD at week 12 and 10 of the 15 patients (66.7%) showed irPD at week 12. For 2 of the 15 patients (13.3%) the end of treatment visit including tumor assessment was performed before week 12 due to progressive disease requiring another systemic treatment (Table 4). Therefore the irDCR at week 12 amounts to 20.0%:
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End point type |
Primary
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End point timeframe |
12 weeks
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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: Statistical analysis can be found in the attached publication |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Immune –related Overall Response Rate (irORR) at week 12 | ||||||||||||
End point description |
Immune –related Overall Response Rate (irORR) at week 12 is defined as the sum of patients with an Overall Response (irPR or irCR) at week 12, divided by the total number of patients who
were evaluable for efficacy. Since none of the 15 evaluable patients showed irCR or irPR at week 12 (Table 4), the irORR at
week 12 was 0%
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End point type |
Secondary
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End point timeframe |
12 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Immune-related Best Overall Response Rate (irBORR) | ||||||||||||
End point description |
Immune-related Best Overall Response Rate (irBORR) is defined as number of patients whose irBOR was irCR (Complete Response) or irPR (Partial Response), divided by the total number of patients who were evaluable for efficacy. Of the 15 evaluable patients none of them showed irCR or irPR as Best Response. Therefore the irBORR is 0%.
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End point type |
Secondary
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End point timeframe |
12 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
ORR at week 12 according to modified WHO criteria (mWHO) | ||||||||||||
End point description |
This secondary endpoint represents the sum of patients with an overall response (CR or PR) according to modified WHO criteria) at week 12, divided by the total number of patients, who
were evaluable for efficacy. 15 patients were evaluable for the analysis. 1 of the 15 patients (6.67%) showed SD (Stable Disease) according to mWHO criteria at week 12 and
12 of the 15 patients (80.0%) showed PD according to mWHO at week 12. For 2 of the 15 patients (13.3%) the end of treatment visit including tumor assessment was performed before week 12 due to progressive disease requiring another systemic treatment. Since none of the 15 evaluable patients showed CR or PR (according to mWHO) at week 12, the ORR at week 12 according to modified WHO criteria was 0%.
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End point type |
Secondary
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End point timeframe |
12 weeks
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Adverse events were assessed at each visit during the treatment period and at week 52
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Adverse event reporting additional description |
Safety laboratory tests had to be documented at the pre-study visit, at days 1, 8, 15, 22, 29, 44, and 65 of the treatment period and at week 12.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
NCI CTCAE | ||
Dictionary version |
4
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| Frequency threshold for reporting non-serious adverse events: 4% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Information regarding Adverse Events and Serious AEs can be found in the attached file |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
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. | |||
| After analysis of the first 15 patients , an unsatisfactory efficacy (irDCR at week 12: 20.0%) became aware. Therefore the second part of the study involving additional 24 patients was omitted. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/2800845 |
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