Clinical Trial Results:
A Study of the Safety and Efficacy of IMM-101 in Combination with Checkpoint Inhibitor Therapy in Patients with Advanced Melanoma
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Summary
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EudraCT number |
2018-001346-34 |
Trial protocol |
GB |
Global end of trial date |
02 Dec 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Dec 2022
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First version publication date |
15 Dec 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
IMM-101-015
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03711188 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Immodulon Therapeutics Ltd
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Sponsor organisation address |
6-9 The Square, Stockley Park, Uxbridge, United Kingdom, UB11 1FW
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Public contact |
Clinical Trial Information Desk, Immodulon Therapeutics Ltd, 0044 0203137 6346, info@immodulon.com
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Scientific contact |
Clinical Trial Information Desk, Immodulon Therapeutics Ltd, 0044 0203137 6346, info@immodulon.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 |
02 Dec 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Jun 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Dec 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
• To evaluate Overall Response Rate (ORR) after a maximum of 18 months treatment, in patients with advanced melanoma receiving IMM-101 plus nivolumab. ORR in both previously untreated patients (cohort A) and in patients whose disease has progressed during PD-1 blockade (cohort B) will be evaluated using RECIST 1.1. ORR will also be assessed for subgroups based on PD-L1 status (positive or negative/undetermined) in cohort A patients.
• To evaluate the safety and tolerability of the combination of IMM-101 plus nivolumab in patients with advanced melanoma by examining the profile of adverse events experienced.
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Protection of trial subjects |
IMM-101, in pancreatic cancer studies has been shown,when co-administered with gemcitabine, to provide clinically relevant survival benefits and improvements in progression free survival. The safety data indicated that this was achieved without significant additional toxicity. As such the risk/benefit for further evaluation in other cancer indications was considered favourable.
An interim data review was performed for cohort B patients.
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Background therapy |
Nivolumab was to be given as 3 mg/kg intravenous (IV) infusion every 2 weeks, 240 mg IV infusion every 2 weeks or 480 mg IV infusion every 4 weeks, according to the prescribing information in both Cohort A and Cohort B. If used on study for patients in Cohort B, ipilimumab was to be administered as a 3 mg/kg IV infusion over 90 minutes every 3 weeks for a maximum of 4 doses, in accordance with the prescribing information | ||
Evidence for comparator |
Not applicable - this was not a comparative study. I | ||
Actual start date of recruitment |
17 Sep 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
United Kingdom: 16
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Worldwide total number of subjects |
16
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EEA total number of subjects |
0
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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) |
6
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From 65 to 84 years |
9
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85 years and over |
1
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Recruitment
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Recruitment details |
Patients who provided informed consent participated in a Screening period of up to a maximum of 21 days to establish eligibility. Sixteen patients were deemed to have met the eligibility criteria and were treated between 04-Oct-2018 and 06-May-2021. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Twenty-two patients at 2 centres were consented and screened. Six patients failed to meet one or more of the specific inclusion criteria or met one or more exclusion criteria and were deemed screen failures. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (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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Are arms mutually exclusive |
Yes
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Arm title
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Cohort A | ||||||||||||||||||
Arm description |
Patients in cohort A were treatment-naive and were required to have had a tumour sample (archived tissue in the last 3 months or newly obtained biopsy) that was adequate for PD-L1 assessment prior to enrolment. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Heat killed whole cell M. obuense NCTC 13365
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Investigational medicinal product code |
IMM-101
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
All patients in both cohorts of the study were to receive one dose of IMM-101 every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then every 2 weeks for the next 3 doses, and thereafter every 4 weeks.
IMM-101 (10 mg/mL) was to be administered as a single 0.1 mL intradermal injection (10 mg/mL) into the skin overlying the deltoid muscle, with the arm being alternated between each dose.
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Arm title
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Cohort B | ||||||||||||||||||
Arm description |
Patients in cohort B were either currently on (or had previously received) treatment with an anti-PD-1 therapy (monotherapy or in combination) for advanced melanoma and had progressive disease by RECIST 1.1 after at least 3 doses of anti-PD-1 given as monotherapy or at least 2 doses of anti-PD-1 given in combination regimes and had not received any therapy since for advanced melanoma. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Heat killed whole cell M. obuense NCTC 13365
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Investigational medicinal product code |
IMM-101
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
All patients in both cohorts of the study were to receive one dose of IMM-101 every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then every 2 weeks for the next 3 doses, and thereafter every 4 weeks.
IMM-101 (10 mg/mL) was to be administered as a single 0.1 mL intradermal injection (10 mg/mL) into the skin overlying the deltoid muscle, with the arm being alternated between each dose.
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
All patients in either cohort who received at least one dose of IMM-101 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort A
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Reporting group description |
Patients in cohort A were treatment-naive and were required to have had a tumour sample (archived tissue in the last 3 months or newly obtained biopsy) that was adequate for PD-L1 assessment prior to enrolment. | ||
Reporting group title |
Cohort B
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Reporting group description |
Patients in cohort B were either currently on (or had previously received) treatment with an anti-PD-1 therapy (monotherapy or in combination) for advanced melanoma and had progressive disease by RECIST 1.1 after at least 3 doses of anti-PD-1 given as monotherapy or at least 2 doses of anti-PD-1 given in combination regimes and had not received any therapy since for advanced melanoma. | ||
Subject analysis set title |
Cohort A PD-L1 Positive at screening
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subgroups of patients in cohort A were defined based on PD-L1 status (PD-L1 positive and PD-L1 negative/indeterminate) at Screening. For one patient PD-L1 status was unknown.
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Subject analysis set title |
Cohort A PD-L1 Negative/indeterminate at screening
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subgroups of patients in cohort A were defined based on PD-L1 status (PD-L1 positive and PD-L1 negative/indeterminate) at Screening.
The PD-L1 status of one patient was unknown
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End point title |
Safety [1] | |||||||||||||||||||||
End point description |
Incidence, frequency and severity of treatment emergent adverse events (TEAEs) throughout the study. This included all TEAEs, SAEs, treatment-related TEAEs, immune-related AEs, Grade 3 and above TEAEs and TEAEs leading to IMM-101 discontinuation or study withdrawal.
A total of 120 full doses of IMM-101 were administered to patients in cohort A and 30 full doses to patients in cohort B.
The median (range) total exposure to nivolumab per patient in cohort A was 3360 (360 to 11200) mg and per patient in cohort B was 880 (640 to 4020) mg.
Only one patient, Patient 01-201 in cohort B, received ipilimumab (one infusion of 175 mg).
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End point type |
Primary
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End point timeframe |
From the point of Informed Consent until withdrawal from the study or the end of study assessment.
All 16 patients enrolled had at least one dose of IMM-101 and nivolumab.
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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: There was no statistical analysis on this primary endpoint Descriptive evaluation of efficacy and safety endpoints was performed using summary statistics for continuous data endpoints and frequency counts and percentages for categorical data endpoints. All study data were presented as data listings |
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End point title |
Overall Response Rate (ORR) [2] | |||||||||||||||||||||||||||
End point description |
Overall Response Rate (ORR) was calculated from the Best overall Response (BOR) of patients as assessed by RECIST 1.1.
Due to the small number of patients in this study, the 95% CIs for the response rate estimates are correspondingly wide and hence results should be interpreted with caution.
The ORR was 73% (95% CI 39, 94) in cohort A. Two of these patients were complete responders. All patients in cohort B reported progressive disease.
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End point type |
Primary
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End point timeframe |
From Informed consent until death, withdrawal from study or after a maximum of 18 months treatment (End of Study)
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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: There was no statistical analysis on this primary endpoint Descriptive evaluation of efficacy and safety endpoints was performed using summary statistics for continuous data endpoints and frequency counts and percentages for categorical data endpoints. All study data were presented as data listings |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Progression free survival (PFS) | ||||||||||||||||||||||||||||||
End point description |
Progression-free survival was defined as the time from Visit 1 (week 0) and the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). Progression was determined by the investigator using the CT or MRI scan or death due to any cause. Patients who died without reporting progression were considered to have progressed on the date of their death.
The median PFS time for Cohort A was 10.2 months (95% CI 3 months, not evaluable [NE]). Over 50% of the cohort A patients were progression-free for at least 9 months and 41% were progression-free for at least 18 months.
No patients in Cohort B had a response to treatment so median PFS was not evaluable.
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End point type |
Secondary
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End point timeframe |
From Visit 1 (week 0) and the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first).
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Overall Survival (OS) | ||||||||||||||||||||||||||||||
End point description |
Overall survival was defined as the time from Visit 1 (week 0) until date of death from any cause. OS was calculated for the entire study duration, where patients without a death date were right censored at the date the patient was last known to be alive. Post-study survival information was collected until database lock, for subjects completing or withdrawing from the study and included in the analysis.
In cohort A, One patient died whilst on study and three patients died during post- study follow up. The remaining seven patients were known to be alive at last contact which varied between 55 days and 2.5 years post-study. The median OS time was not calculable for cohort A as less than 50% patients died.
In cohort B, all five patients died between 4 and 7 months after withdrawing from the study. The median OS time for patients in cohort B was 9.7 months (95% CI 6, NE).
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End point type |
Secondary
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End point timeframe |
Overall survival was defined as the time from Visit 1 (week 0) until date of death from any cause. OS was calculated for the entire study duration, where patients without a death date were right censored at the date the patient was last known to be alive.
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Overall Response Rate based on PD-L1 status at screening | ||||||||||||
End point description |
For cohort A a subgroup analysis of overall response rate was conducted according to PD-L1 status at screening.
Objective response rate is calculated as the number of patients with a best objective response of complete response or partial response divided by the number of patients in the analysis set.
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End point type |
Other pre-specified
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End point timeframe |
From informed consent to study completion or withdrawal
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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 |
Adverse events were collected from the point of Informed Consent until withdrawal from the study or the end of study assessment.
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Adverse event reporting additional description |
Treatment emergent adverse events (TEAEs) were defined as AEs occurring at or after the first IMM-101 dose These included all TEAEs, SAEs, treatment-related TEAEs, immune-related AEs, Grade 3 and above TEAEs and TEAEs leading to IMM-101 discontinuation or study withdrawal.
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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 |
21.0
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Reporting groups
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Reporting group title |
Safety Analysis Set
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Reporting group description |
The Safety Analysis Set included all patients who received at least one dose of IMM-101, irrespective of compliance with eligibility and other protocol criteria. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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16 Dec 2019 |
The original protocol (Version 1.0) was dated 09 April 2018.
Version 2.0 of the protocol, dated 16 December 2019, was considered to be a substantial protocol amendment and included:
* Amendment of the inclusion criterion that specified the number of doses of prior treatment with anti-PD-1 therapy that were required for cohort B of the study.
* Removal of the exclusion criterion that limited the number of treatment regimens allowed prior to anti-PD-1 therapy to one, for patients enrolling in cohort B of the study.
* Amendment of dosing schedule of nivolumab to accommodate an investigator choice between 3 mg/kg every 2 weeks, 240 mg every 2 weeks or 480 mg every 4 weeks.
* Change of time between end of other investigational product and first study dose from 4 weeks to 3 weeks.
* Number of sites increased from 1 to 3-4 sites
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| The ORR in Cohort A compared favourably with those seen in a similar population treated with nivolumab only, although the sample size is small in this non-comparative study and this finding would need to be confirmed in larger studies. | |||||||
