Clinical Trial Results:
A multicenter, open label Phase I/II study to determine the safety and immune modulating effects of the therapeutic Human Papilloma Virus Type 16 (HPV16) E6/E7 Synthetic Long Peptides Vaccine (ISA101/ISA101b) immunotherapy in combination with standard of care therapy (carboplatin and paclitaxel with or without bevacizumab) in women with HPV16-positive advanced or recurrent cervical cancer who have no curative treatment options.
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Summary
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EudraCT number |
2013-001804-12 |
Trial protocol |
DE NL BE |
Global end of trial date |
01 Sep 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Oct 2019
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First version publication date |
24 Oct 2019
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Other versions |
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Summary report(s) |
ISA_Clinical Study Report_Synopsis_V1.0_09Aug2019 |
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 |
ISA-HPV-01-12
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02128126 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
ISA Therapeutics B.V.
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Sponsor organisation address |
J.H. Oortweg 19, Leiden, Netherlands, 2333 CH
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Public contact |
Sonja Visscher, ISA Therapeutics B.V., info@isa-pharma.com
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Scientific contact |
Kees Melief , ISA Therapeutics B.V., melief@isa-pharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Oct 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Aug 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Sep 2018
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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 objectives of this trial were:
To assess the safety and tolerability of different doses of the ISA101 vaccine with or without pegylated Interferon Alpha (IFNα) as combination therapy with carboplatin and paclitaxel.
To assess the HPV-specific immune responses to different doses of the ISA101 vaccine with or without pegylated IFNα as combination therapy with carboplatin and paclitaxel.
To qualitatively assess the safety profile of ISA101b vaccine compared to ISA101 at the same dose level(s).
To assess the safety of ISA101b vaccine with carboplatin, paclitaxel with or without bevacizumab.
To qualitatively assess the HPV-specific immune responses of ISA101b vaccine relative to the same dose level(s) of ISA101.
To qualitatively assess the HPV-specific immune responses of ISA101b vaccine with carboplatin, paclitaxel with or without bevacizumab.
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Protection of trial subjects |
Patients receiving ISA101(b) were closely monitored for at least 4 hours after vaccination to provide means for immediate treatment of allergic reactions should that be necessary (precautions include availability of staff well-trained in resuscitation, intravenous access for administration of fluids, antihistamines and corticosteroids, and epinephrine for intramuscular injection).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Aug 2013
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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 |
Belgium: 45
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Country: Number of subjects enrolled |
Netherlands: 44
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Country: Number of subjects enrolled |
Germany: 1
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Worldwide total number of subjects |
90
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EEA total number of subjects |
90
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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) |
81
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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 |
This trial was conducted in 13 centers in 3 countries: Belgium, The Netherlands and Germany. First ICF was signed: 15Aug2013. Last study visit before database lock: 09May2018 | ||||||||||||||||||
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Pre-assignment
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Screening details |
Patients with advanced (Stage IIIb-IVa with involvement of lymph nodes beyond the renal vein) or metastatic (stage IVb) or recurrent HPV16-positive cervical cancer for whom no curative treatment options existed were enrolled. Total number of patients registered was 93 with 90 being part of safety set. | ||||||||||||||||||
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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 | ||||||||||||||||||
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Arms
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Arm title
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ISA101/ISA101b with SoC therapy | ||||||||||||||||||
Arm description |
Synthetic Long Peptides Vaccine (ISA101/ ISA101b) immunotherapy in combination with standard of care therapy (carboplatin and paclitaxel with or without bevacizumab). * Stage 1: 8 cohorts of 6 patients each, 4 dose levels of ISA101 (20, 40, 100 and 300 μg/peptide) with and without 1 μg/kg pegylated IFNα in combination with fixed doses of Standard of Care (SoC) chemotherapy: carboplatin at an AUC of 6 mg/ml/min and paclitaxel at a dose of 175 mg/m2. * Stage 2: 6 additional patients were enrolled each at 40 and 100 μg/peptide dose level of ISA101, without pegylated IFNα. * Stage 3: ISA101b was tested using the RP2D of 100 μg/peptide. 6 patients were enrolled at the dose level of 100 μg/peptide (cohort 9) in which the dose was given in conjunction with carboplatin at an AUC of 6mg/ml/min and paclitaxel; 6 more patients were treated with ISA101b at 100 μg/peptide in addition to carboplatin, paclitaxel, AND bevacizumab | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
ISA101/ISA101b
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Patients eligible for the trial were assigned to a cohort in order of entry. Each patient was to receive 3 doses of vaccine (ISA101 or ISA101b) over nine weeks in Cycles 2, 3 and 4 of a total of up to six cycles of chemotherapy (18 weeks, without dose interruption/delays)
The ISA101 vaccine contains nine HPV16 E6 and four HPV16 E7 SLP.
The peptides were dissolved in DMSO and subsequently diluted in WFI and emulsified with Montanide. The final ratio of DMSO / WFI / Montanide is 20/30/50.
The ISA101b vaccine contains nine HPV16 E6 and three HPV16 E7 SLP.
The peptides are reconstituted with Macrogolglycerol Ricinoleate (Reconstitution Solution) and mixed with Montanide
The ISA101/ISA101b vaccine is administered via two SC injections in two different limbs.
Stage 1: four dose levels of ISA101 (20, 40, 100 and 300 μg/peptide)
Stage 2: 40 and 100 μg/peptide dose level of ISA101,
Stage 3: ISA101b of 100 μg/peptide.
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Investigational medicinal product name |
Pegnitron
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Investigational medicinal product code |
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Other name |
pegylated interferon alpha
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Pharmaceutical forms |
Powder for solution for injection, Solution for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Pegintron is administered SC according to the SPC
Stage 1: with and without 1 μg/kg pegylated IFNα
Stage 2: without pegylated IFNα
Stage 3: without pegylated IFNα
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Investigational medicinal product name |
Paclitaxel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Stage 1: fixed doses of Standard of Care (SoC) chemotherapypaclitaxel at a dose of 175 mg/m2.
Stage 2: fixed doses of Standard of Care (SoC) chemotherapypaclitaxel at a dose of 175 mg/m2. with and without bevacizumab
Stage 3: fixed doses of Standard of Care (SoC) chemotherapypaclitaxel at a dose of 175 mg/m2.
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Investigational medicinal product name |
Carboplatin
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Investigational medicinal product code |
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Other name |
cis-Diammine(1,1-cyclobutanedicarboxylato)platinum
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Stage 1: dose of Standard of Care (SoC) chemotherapy: carboplatin at an Area Under the Curve (AUC) of 6 mg/ml/min
Stage 2: dose of Standard of Care (SoC) chemotherapy: carboplatin at an Area Under the Curve (AUC) of 6 mg/ml/min
Stage 3: dose of Standard of Care (SoC) chemotherapy: carboplatin at an Area Under the Curve (AUC) of 6 mg/ml/min
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Investigational medicinal product name |
Avastin
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Investigational medicinal product code |
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Other name |
bevacizumab
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Stage 1 & 2: No bevacizumab
Stage 3: in cohort 10 only, bevacizumab 15 mg/kg per standard of care
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
the total number of patients registered in the trial was 93 with 90 being part of the SAF (Safety set) population because 3 patients never received any trial treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Subjects who received at least 1 dose of ISA101/ISA101b
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The total number of patients receiving at least one dose of ISA101
vaccination was 72 and another 12 patients received at least one dose of ISA101b vaccine.
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Subject analysis set title |
Subjects for ISA101
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
SAF-ISA101 Population is 77 (cohort 1 - 8) note: 5 of them never received any dose of ISA101
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Subject analysis set title |
Subjects for ISA101b
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
SAF-ISA101 Population is 13 (cohort 9-10)
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End points reporting groups
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Reporting group title |
ISA101/ISA101b with SoC therapy
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Reporting group description |
Synthetic Long Peptides Vaccine (ISA101/ ISA101b) immunotherapy in combination with standard of care therapy (carboplatin and paclitaxel with or without bevacizumab). * Stage 1: 8 cohorts of 6 patients each, 4 dose levels of ISA101 (20, 40, 100 and 300 μg/peptide) with and without 1 μg/kg pegylated IFNα in combination with fixed doses of Standard of Care (SoC) chemotherapy: carboplatin at an AUC of 6 mg/ml/min and paclitaxel at a dose of 175 mg/m2. * Stage 2: 6 additional patients were enrolled each at 40 and 100 μg/peptide dose level of ISA101, without pegylated IFNα. * Stage 3: ISA101b was tested using the RP2D of 100 μg/peptide. 6 patients were enrolled at the dose level of 100 μg/peptide (cohort 9) in which the dose was given in conjunction with carboplatin at an AUC of 6mg/ml/min and paclitaxel; 6 more patients were treated with ISA101b at 100 μg/peptide in addition to carboplatin, paclitaxel, AND bevacizumab | ||
Subject analysis set title |
Subjects who received at least 1 dose of ISA101/ISA101b
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The total number of patients receiving at least one dose of ISA101
vaccination was 72 and another 12 patients received at least one dose of ISA101b vaccine.
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Subject analysis set title |
Subjects for ISA101
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
SAF-ISA101 Population is 77 (cohort 1 - 8) note: 5 of them never received any dose of ISA101
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Subject analysis set title |
Subjects for ISA101b
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
SAF-ISA101 Population is 13 (cohort 9-10)
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End point title |
Subjects With at Least One TEAE (Treatment-Emergent Adverse Ev, TEAE Related to ISA101(b), TEAE Related to IFNa, TEAE Related to Chemotherapy, TEAE Related to Bevacizumab, Serious TEAE, TEAE of NCI-CTC Grade 3, 4, or 5, and TEAE Leading to Drug Withdrawal [1] | ||||||||||||||||||||||||
End point description |
A TEAE was reported in 89 out of 90 patients. The one patient without any TEAEs experienced rapid progression after the first chemotherapy cycle, this patient did not received any dose ISA101(b). The reported AE was “increased pain”, which was not related to any therapy and started before the first chemotherapy administration.
Almost all patients (98.9%) reported chemotherapy related AEs. AEs related to ISA101/ISA101b were reported for 80.0% of all patients, with a somewhat lower frequency of vaccine-related events recorded for the ISA101b bridging cohorts compared with the ISA101 cohorts at the same peptide concentration of 100 μg/peptide, 69.2% versus 100% respectively.
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End point type |
Primary
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End point timeframe |
The study will include 3 weeks of screening, 18 weeks of treatment, 30-day follow up after treatment for safety, and 34 weeks follow up after treatment for clinical response
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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 analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Treatment-Emergent Systemic Allergic Reactions (TESAR) Related to ISA101(b):Subjects With at Least One TESAR, Serious TESAR, TESAR of NCI-CTC Grade 3, 4, or 5, and TESAR Leading to Drug Withdrawal [2] | ||||||||||||||||||
End point description |
Overview of Reported TESAR ((treatment emergent serious allergic reaction) Related to ISA101/ISA101b
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End point type |
Primary
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End point timeframe |
The study will include 3 weeks of screening, 18 weeks of treatment, 30-day follow up after treatment for safety, and 34 weeks follow up after treatment for clinical response
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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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Treatment-Emergent Injection Site Reactions (TEISR) related to ISA101(b): subjects With at Least One TEISR , Serious TEISR, TEISR of NCI-CTC Grade 3, 4, or 5, and TEISR Leading to Drug Withdrawal of Patients Treated with ISA101/ISA101b [3] | ||||||||||||||||||
End point description |
Treament emergent dose-related Injection Site Reactions (ISRs) to ISA101 were the most frequent AEs reported to be related to ISA101 with ISRs occurring in most patients who received ISA101. Most of the local ISRs were
reported to be Grade 1 to 2 in severity.
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End point type |
Primary
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End point timeframe |
The study will include 3 weeks of screening, 18 weeks of treatment, 30-day follow up after treatment for safety, and 34 weeks follow up after treatment for clinical response.
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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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
HPV specific immune response to the ISA101 vaccine [4] | ||||||||||||||||||||
End point description |
See CSR synopsis in attachment page 7 for description of Biomarker Response - Immune Response to ISA101/ISA101b
Spearman correlation
r = correlation coefficient
MRM = Memory Response Mix; ESM = maximum of MRM at visits 8 and 10; ESMC = maximum of MRM at Visit 8 and 10 - MRM at Visit 4; ESMCP = 100*(ESM - MRM at visit4)/MRM at visit 4
ESSMEDIAN = for each of the 6 epitopes the maximum over visit 8 and 10. ESSMEDIAN is the median of the 6 maxima.
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End point type |
Primary
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End point timeframe |
The study will include 3 weeks of screening, 18 weeks of treatment, 30-day follow up after treatment for safety, and 34 weeks follow up after treatment for clinical response
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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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
IMMUNE OUTCOME DATA [5] | ||||||||||||||||||||||||||
End point description |
ESM = maximum of MRM at visits 8 and 10
MRM = Memory Response Mix
ESSMEDIAN = for each of the 6 epitopes the maximum over visit 8 and 10. ESSMEDIAN is the median of the 6 maxima
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End point type |
Primary
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End point timeframe |
The study will include 3 weeks of screening, 18 weeks of treatment, 30-day follow up after treatment for safety, and 34 weeks follow up after treatment for clinical response
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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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Best Overall Response | ||||||||||||||||
End point description |
Patients who had a stronger HPV16-specific immune response to ISA101 (greater than or equal to the median) had a statistically significant prolongation of median OS of 16.8 months compared to those who had a lower HPV-specific immune response (median OS of 11.2 months). These data indicate a strong association between the strength of the HPV-specific immune response induced by ISA101 treatment and OS.
Patients who had a stronger HPV16-specific immune response to ISA101 (greater than or equal to the median) had a statistically significant prolongation of median OS of 16.8 months compared to those who had a lower HPV-specific immune response (median OS of 11.2 months). These data indicate a strong association between the strength of the HPV-specific immune response induced by ISA101 treatment and OS.
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End point type |
Secondary
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End point timeframe |
CT/MRI scan at baseline, Day 1 of cycle 4, EoT visit and at week 30, 42, 52
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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 |
Patients were monitored for AEs from Inform Consent Form signature and during each patient visit until 30 days after end of treatment visit.
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Adverse event reporting additional description |
All reported (S)AEs are the (S)AEs with the onset of first treatment.
In this data base only events related to ISA101(b) are reported.
Most of the (S)AEs in the CervISA trial were expected toxicities related to chemotherapy or to complications associated with progression of cervical cancer.
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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 |
17.0
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Reporting groups
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Reporting group title |
received at least one dose of ISA101 group
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Reporting group description |
A total of 93 patients registered for the trial, 79 for the evaluation of ISA101 and 14 for the ISA101b evaluation. The Safety Set (SAF) for the trial was defined as all patients who received at least one dose of chemotherapy or other trial treatment: For ISA101, the SAF population was 77 patients of whom 72 received at least one dose of ISA101 vaccine and 51 patients completed all trial related treatments. For ISA101b, the SAF population was 13 patients, 12 of whom received at least one dose of ISA101b vaccine and seven completed all study related treatments. Most of the (S)AEs in the CervISA trial were expected toxicities related to chemotherapy or to complications associated with progression of cervical cancer. Only ISA101 related (S)AE are reported in this database | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
received at least one dose of ISA101b group
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Reporting group description |
A total of 93 patients registered for the trial, 79 for the evaluation of ISA101 and 14 for the ISA101b evaluation. The Safety Set (SAF) for the trial was defined as all patients who received at least one dose of chemotherapy or other trial treatment: For ISA101, the SAF population was 77 patients of whom 72 received at least one dose of ISA101 vaccine and 51 patients completed all trial related treatments. For ISA101b, the SAF population was 13 patients, 12 of whom received at least one dose of ISA101b vaccine and seven completed all study related treatments. Most of the (S)AEs in the CervISA trial were expected toxicities related to chemotherapy or to complications associated with progression of cervical cancer. Only ISA101(b) related (S)AE are reported in this database. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Jun 2013 |
Protocol V2.0 Initial approved protocol Belgium (BE) |
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09 Jan 2014 |
Protocol V2.1, Initial approved protocol the Netherlands (NL) |
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11 Jul 2014 |
protocol V3.0 , Approved for BE and NL |
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14 Jul 2015 |
Protocol V4.0, Approved for BE and NL |
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22 Oct 2015 |
Protocol V5.0, Approved for BE and NL |
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21 Jan 2016 |
Protocol V6.0, Approved for BE and NL |
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24 Jun 2016 |
Protocol V7.0, Approved for BE and NL |
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05 Aug 2016 |
Protocol V8.0, Initial approved protocol Germany (DE) |
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27 Oct 2016 |
Protocol V9.0, Approved for BE, NL and DE |
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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. | |||
| None reported | |||
