Clinical Trial Results:
A phase I/II trial of IMA970A plus CV8102 following a single pre-vaccination infusion of cyclophosphamide in patients with very early, early and intermediate stage of hepatocellular carcinoma after any standard treatments
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Summary
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EudraCT number |
2015-003389-10 |
Trial protocol |
DE BE ES IT |
Global end of trial date |
20 Dec 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Apr 2021
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First version publication date |
07 Apr 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 |
HepaVac-101
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT03203005 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
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Sponsor organisation address |
Via Mariano Semmola 142, Naples, Italy, 80131
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Public contact |
Clinical Trial Information, HepaVac Consortium @ Istituto Nazionale Tumori G. "Pascale", 0039 0815903624, info@hepavac.eu
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Scientific contact |
Clinical Trial Information, HepaVac Consortium @ Istituto Nazionale Tumori G. "Pascale", 0039 0815903624, info@hepavac.eu
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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 |
20 Dec 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 Dec 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Dec 2019
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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 primary objective of the present phase I/II study is to investigate whether treatment with IMA970A plus CV8102 following a single pre-vaccination infusion of cyclophosphamide (CY) is safe and tolerable, and able to induce a T-cell response in very early, early and intermediate stage hepatocellular carcinoma (HCC) patients after any standard treatment and without any evidence of active disease that warrant further treatment.
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Protection of trial subjects |
The study was performed in accordance with Declaration of Helsinki, International Council on Harmonization/GCP guidelines and all applicable and ethical regulatory requirements. The study was approved by national regulatory agencies and the Independent Ethics Committee (IEC) competent for the coordinating investigator and the IECs responsible for each study site in accordance with the local legislation in each participating country.
All subjects were fully informed about nature, scope and possible consequences of the clinical trial in a language appropriate for the subject and they provided written informed consent before study-related procedures were performed.
Following precautionary safety measures were implemented into the trial to assure the safety of patients:
- Facilities and equipment for resuscitation have to be in place when performing vaccinations with IMA970A and CV8102 to shorten reaction times in case of life- threatening anaphylactic reactions.
- Staggered enrollment of the first 3 patients
- Early Data Safety Monitroing Board (DSMB) meeting, regular DSMB meetings throughout the trial and ad hoc DSMB meetings
- Reporting of adverse events of special interest (AESIs) according to the reporting rules of serious adverse events
- Dose de-escalation rules for CV8102 are implemented into the clinical trial for patients experiencing CTCAE Grade ≥ 3 adverse drug reactions
- Premature withdrawal from study treatment in case of unacceptable toxicities
- Capturing of selected safety data including autoimmune diseases, adverse drug reactions and outcome after liver transplantation during non-interventional follow-up
- Patients with a history of or active autoimmune diseases were excluded from treatment with IMA970A and CV8102.
Additionally, special precautions for IMA970A and CV8102 vaccinations and CY treatment were specified in detail in the protocol and the Investigator's Brochure and explained to investigators during Site Initiation.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Oct 2017
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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 |
Spain: 1
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Italy: 14
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Worldwide total number of subjects |
22
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EEA total number of subjects |
22
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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) |
10
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From 65 to 84 years |
12
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85 years and over |
0
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Recruitment
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Recruitment details |
Between 2017 and 2019, 82 patients were screened at six study centers in Italy, Germany, Belgium, The United Kingdom, and Spain of whom 22 were assigned to receive study treatment. | ||||||||||||
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Pre-assignment
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Screening details |
In Screening S1, patients were screened for HLA typing, demographics and disease characteristics either before (S1.1) or during (S1.2) standard treatment for HCC and recovery phase. Still eligible patients entered the main Screening S2 for final eligibility check and baseline assessments (e.g. CT/MRI, medical history, blood sampling, ECG, ECOG). | ||||||||||||
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Period 1
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Period 1 title |
Overall trial (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 | ||||||||||||
Blinding implementation details |
No blinding procedures were performed in this open-label, single arm trial.
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Arms
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Arm title
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Trial Treatment (IMA970A, CV8102 and CY) | ||||||||||||
Arm description |
Within this single arm trial to investigate safety, tolerability and immunogenecity , all eligible patients were assigned to receive a pre-treatment wirh CY followed by vaccinations with IMA970A and CV8102. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
IMA970A
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Investigational medicinal product code |
IMA970A
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
IMA970A is a cocktail of 17 synthetic TUMAPs with the ability to elicit T-cell responses. It consists of 7 human HLA-A*02 Class I-binding peptides, 5 HLA-A*24 Class I-binding peptides, 4 HLA-DR Class II-binding peptides, and 1 HLA-A*02 Class I-binding peptide from HBV core antigen (marker peptide). The dose per each intradermal vaccination was 400 μg of each peptide. Overall, a total of 9 vaccinations were scheduled; the first 4 vaccinations were applied at weekly intervals (Days 1, 8, 15, and 22), and the remaining 5 vaccinations were given in 3-weekly intervals (Days 43, 64, 85, 106, and 127). All vaccinations were preferably to be applied intradermally to the same initially selected vaccination site (the skin of the inner side of the thighs or the upper arms) in order to target the same draining lymph nodes with all vaccinations. IMA970A was to be injected first, followed by CV8102 as close as possible to the injection site of IMA970A about 10 minutes later.
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Investigational medicinal product name |
CV8102
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Investigational medicinal product code |
CV8102
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Other name |
RNAdjuvant
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
CV8102 is a novel RNA-based immuno-stimulatory adjuvant. It is composed of a purified, single-stranded, non-coding, long-chain RNA (R2025) and a small, arginine-rich cationic peptide (CR12C) that form particles (complexes) of approximately 100 nm size optimized for enhanced immune-stimulatory activity. The starting dose was 50 µg per intradermal injection, which could be reduced to 25 µg in the case of intolerability.Overall, a total of 9 vaccinations were scheduled; the first 4 vaccinations were applied at weekly intervals (Days 1, 8, 15, and 22), and the remaining 5 vaccinations were given in 3-weekly intervals (Days 43, 64, 85, 106, and 127). All vaccinations were preferably to be applied intradermally to the same initially selected vaccination site (the skin of the inner side of the thighs or the upper arms) in order to target the same draining lymph nodes with all vaccinations. IMA970A was to be injected first, followed by CV8102 10 minutes later.
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Investigational medicinal product name |
Endoxan
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Investigational medicinal product code |
Cyclophosphamide
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Other name |
CY
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cyclophosphamide (CY) is an immunomodulatory agent and was administered intravenously as a single pre-vaccination infusion at a low dose of 300 mg/m2 body surface area in order to enhance the immune response to vaccination by means of reducing inhibitory regulatory T cells.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
Safety analysis set (SAF)
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All enrolled patients having received at least once study drug (i.e. CY, IMA970A, or CV8102)
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Subject analysis set title |
Immune-response evaluable population (IRE)
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients who had received the first 7 vaccinations.
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End points reporting groups
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Reporting group title |
Trial Treatment (IMA970A, CV8102 and CY)
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Reporting group description |
Within this single arm trial to investigate safety, tolerability and immunogenecity , all eligible patients were assigned to receive a pre-treatment wirh CY followed by vaccinations with IMA970A and CV8102. | ||
Subject analysis set title |
Safety analysis set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All enrolled patients having received at least once study drug (i.e. CY, IMA970A, or CV8102)
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Subject analysis set title |
Immune-response evaluable population (IRE)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All patients who had received the first 7 vaccinations.
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End point title |
Safety: Overview of TEAEs by maximum severity [1] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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End point title |
Safety: Overview of SAEs by maximum severity [2] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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| Notes [2] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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End point title |
Safety: Overview of TEAEs leading to any action with any study drug [3] | ||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Safety: Overview of TEAEs by relation to study drugs [4] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
'Study drug' includes IMA970A, CV8102 and CY.
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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| Notes [4] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Safety: Overview of SAEs by relation to study drugs [5] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
'Study drug' includes IMA970A, CV8102 and CY.
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Safety: Overview of TEAEs related to CY, IMA970A and/or CV8102 by maximum severity [6] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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| Notes [6] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Safety: Overview of TEAEs related to IMA970A and/or CV8102 by maximum severity [7] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
The causality assessments made for IMA970A and CV8102 separately were almost always identical.
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End point type |
Primary
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End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
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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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Safety: Overview of TEAEs related to CY by maximum severity [8] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
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End point type |
Primary
|
||||||||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||||||||
| Notes [8] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Safety: Overview of SAEs related to CY, IMA970A and/or CV8102 by maximum severity [9] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||||||||
| Notes [9] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Safety: Overview of SAEs related to IMA970A and/or CV8102 by maximum severity [10] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
The causality assessments made for IMA970A and CV8102 separately were almost always identical.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||||||||
| Notes [10] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Safety: Overview of SAEs related to CY by maximum severity [11] | ||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing),
Repeatedly occurring AEs (i.e., same preferred term) with similar intensity were counted only once in the severity analyses.
Severity grading according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events to (NCI-CTCAE, Version 4.0).
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||||||||
| Notes [11] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Safety: All TEAEs by System of Organ Class (SOC), if at least 2 patients were involved [12] | ||||||||||||||||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing).
Repeatedly occurring AEs (i.e., same SOC) were counted only once.
|
||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||||||||||||||||||||||
| Notes [12] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Safety: All TEAEs by Preferred Term (PT), if at least 2 patients were involved [13] | ||||||||||||||||||||||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing).
Repeatedly occurring AEs (i.e., same preferred term) were counted only once
|
||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||||||||||||||||||||||||||||
| Notes [13] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||
End point title |
Safety: All TEAEs related to IMA970A and/or CV8102 by SOC, if at least 2 patients were involved [14] | ||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing).
Repeatedly occurring AEs (i.e., same SOC) were counted only once
|
||||||||||
End point type |
Primary
|
||||||||||
End point timeframe |
AEs occurring between start of CY and Visit 10/EOV (or last vaccination, if Visit 10/EOV is missing).
|
||||||||||
| Notes [14] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||||||||||
End point title |
Safety: All TEAEs related to IMA970A and/or CV8102 by PT, if at least 2 patients were involved [15] | ||||||||||||||||||||||||||
End point description |
The main safety analysis is based on treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing).
Repeatedly occurring AEs (i.e., same preferred term) were counted only once.
|
||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||
End point timeframe |
All TEAEs by Preferred Term (PT), if at least 2 patients were involved
|
||||||||||||||||||||||||||
| Notes [15] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'safety' and no statistical testing were performed. |
|||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||
|
|||||||||||||||||||||||
End point title |
Tolerability: Evaluation of local tolerability 5 min. after injections [16] | ||||||||||||||||||||||
End point description |
The evaluation of local tolerability was performed in 21 SAF patients (i.e., completely missing data for 1 patient).
|
||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||
End point timeframe |
Pre-defined signs of local reactions (intolerability) were assessed after vaccination at each vaccination day (i.e., both 5 minutes and 2 hours after the CV8102 injection).
|
||||||||||||||||||||||
| Notes [16] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'tolerability' and no statistical testing were performed. |
|||||||||||||||||||||||
|
|||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||
|
|||||||||||||||||||||||
End point title |
Tolerability: Evaluation of local tolerability 2 hours after injection [17] | ||||||||||||||||||||||
End point description |
The evaluation of local tolerability was performed in 21 SAF patients (i.e., completely missing data for 1 patient).
|
||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||
End point timeframe |
Pre-defined signs of local reactions (intolerability) were assessed after vaccination at each vaccination day (i.e., both 5 minutes and 2 hours after the CV8102 injection).
|
||||||||||||||||||||||
| Notes [17] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'tolerability' and no statistical testing were performed. |
|||||||||||||||||||||||
|
|||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||
|
|||||||||||||||
End point title |
Tolerability: Evaluation of systemic tolerability 2 hours after injections [18] | ||||||||||||||
End point description |
The evaluation of systemic tolerability was performed in 21 SAF patients (i.e., completely missing data for 1 patient).
|
||||||||||||||
End point type |
Primary
|
||||||||||||||
End point timeframe |
Pre-defined signs of systemic reactions (intolerability) were assessed after vaccination at each vaccination day (2 hours after the CV8102 injection).
|
||||||||||||||
| Notes [18] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'tolerability' and no statistical testing were performed. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||
End point title |
Immunogenicity: Vaccine-induced TUMAP responses (Class I TUMAPs) [19] | ||||||||||
End point description |
Primary immunomonitoring analysis (immunogenicity of study treatment) was performed in a total of 19 immune-response evaluable (IRE) patients that were evaluable for immune responses to the 12 Class I and 4 Class II TUMAPs contained in IMA970A.
At least one VI response to Class I was observed in 13 (68.4%) patients, respectively; more than one VI response was seen in 7 (36.8%) patients, respectively. Expressed as a total sum, 21 Class I responses (9.2% relative to the 228 Class I TUMAP exposures among the 19 evaluable patients) were mounted by the vaccinations. Mean number of vaccine-induced responses was 1.1 ± 0.9 (Median: 1.0; range: 1 to 3).
Thus, the ex vivo measured immunogenicity of the Class I TUMAPs contained in IMA970A turned out to be rather moderate.
|
||||||||||
End point type |
Primary
|
||||||||||
End point timeframe |
A vaccine-induced (VI) TUMAP response was regarded as "positive", if a positive VI TUMAP response was observed for at least one post-vaccination time point (visit pool).
|
||||||||||
| Notes [19] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'immunogenicity' and no statistical testing were performed. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||
End point title |
Immunogenicity: Vaccine-induced TUMAP responses (Class II TUMAPs) [20] | ||||||||||
End point description |
Primary immunomonitoring analysis (immunogenicity of study treatment) was performed in a total of 19 immune-response evaluable (IRE) patients that were evaluable for immune responses to the 12 Class I and 4 Class II TUMAPs contained in IMA970A.
At least one VI response to Class II TUMAPs were observed in 10 (52.6%) patients; more than one VI response was seen in 5 (26.3%) patients. Expressed as a total sum, 18 Class II responses (23.7% relative to the 76 Class II TUMAP exposures) were mounted by the vaccinations. Mean number of vaccine-induced responses was 0.9 ± 1.1 (Median: 1.0; range: 1 to 3).
Thus, the ex vivo measured immunogenicity of the Class II TUMAPs contained in IMA970A turned out to be rather moderate.
|
||||||||||
End point type |
Primary
|
||||||||||
End point timeframe |
A vaccine-induced (VI) TUMAP response was regarded as "positive", if a positive VI TUMAP response was observed for at least one post-vaccination time point (visit pool).
|
||||||||||
| Notes [20] - 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: All study analyses were done descriptively, i.e., no confirmatory hypothesis testing was performed, during this single-arm first-in-man phase I/II trial. Only descriptive summary analysis for this end point 'immunogenicity' and no statistical testing were performed. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All treatment-emergent AEs (TEAEs) defined as any AE that started or deteriorated on/after the day of the 1st administration of any study medication (i.e. CY pre-treatment 2-4 days before 1st vaccination) until EOV or last vaccination, if EOV is missing.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
AEs were recorded by asking specifically whether patients had noticed any unexpected or unusual symptoms or because of relevant findings in clinical assessments (e.g. blood sampling, vitals signs, phys. examinations). All AEs were documented in CRF; SAEs and AEs of Special Interest (AESIs) were additionally to be reported within 24 hours to sponso
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
|
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|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Safety analysis set (SAF)
|
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Reporting group description |
all enrolled patients having received at least once study drug (i.e. CY, IMA970A, or CV8102) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
15 May 2015 |
With this Amendment, the following changes from the original protocol (Version 1.1) were implemented::
- The protocol was amended to only include patients with Child-Pugh A5-6 and B7 disease. Thus, patients with Child-Pugh B8 and B9 were no longer allowed to be enrolled.
- It was clarified that, according to medical practice, patients with HBV infection should be treated with antiviral therapy before enrolment.
- An additional sentence was added in the section on special precautions for CY to indicate that "Cyclophosphamide should not be administered to patients with a leukocyte count below 2,500 cells/microliter (cells/mm3) and/or a platelet count below 50,000 cells/mm3".
- Administrative changes in study personnel were implemented. |
||
24 Sep 2018 |
The Amendment implemented the following changes from the protocol:
- New Screening 1 sequence to enable S1 during the standard treatment and recovery phase (screening option S1.2 added)
- Exclusion Criterion No. 1 was modified to additionally allow for screening Option 1.2, where patients might have been to sign their first informed consent during or immediately after the standard treatment.
- Time window between screening 1 (S1 procedures according to screening option S1.1) and start of the currently indicated standard treatment was extended by additional 4 weeks.
- Duration of standard treatment and recovery phase, for both screening options S1.1 and S1.2, was extended by additional 4 weeks
- A statement was added that a sample size of about 20 patients would be sufficient to estimate safety- and immunogenicity-related endpoints
- Tumor assessment according to mRECIST is no longer mandatory but optional. Additionally, imaging of pelvis is only mandatory at baseline, thereafter optional, if no lesion was found in this area.
- Enrollment timelines were prolonged to allow patient enrollment as expected.
- The allocation of a patient ID could be done before signing IC1 for individual patients due to organizational needs (e.g., coordination of PBMC sampling).
- The use of use of paracetamol (acetaminophen) for the treatment or prophylaxis of flu-like symptoms was permitted
Further clarifications and minor adjustments that patients were allowed to be re-screened (e.g. for HLA-typing) and to have more than one standard therapy and that inhaled or nasally applied steroids, as well as topical steroids outside the planned vaccination area, during S2 and paracetamol (acetaminophen) for the treatment or prophylaxis of flu-like symptoms were permitted. description of drug preparation/application was improved and more detailed. Minor re-phrasing. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
