Clinical Trial Results:
Phase II trial of atezolizumab (anti-PD-L1) in the treatment of stage IIb-IV mycosis fungoides/sezary syndrome patients relapsed/refractory after a previous systemic treatment (PARCT)
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Summary
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EudraCT number |
2017-003680-35 |
Trial protocol |
GB DE ES AT GR IT |
Global end of trial date |
18 Aug 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jul 2023
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First version publication date |
30 Jul 2023
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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 |
1652-CLTF
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03357224 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
European Organisation for Research and Treatment of Cancer (EORTC)
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Sponsor organisation address |
Avenue E. Mounier 83/11, Brussels, Belgium, 1200
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Public contact |
Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), 0032 27741044, regulatory@eortc.org
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Scientific contact |
Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), 0032 27741044, regulatory@eortc.org
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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 |
07 Feb 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Aug 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Aug 2022
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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 determine the antitumor activity of atezolizumab for patients with refractory or relapsed advanced stages of mycosis fungoides and Sézary syndrome, assessed in terms of the overall response rate, according to EORTC-ISCL-USCLC criteria
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Protection of trial subjects |
The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
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Background therapy |
Trial assessing atezolizumab (anti-PD-L1) as treatment option for patients with mycosis fungoides (MF) /sezary syndrome (SS) having progressed under or after previous therapy. For this study, we invite patients suffering from MF and SS who have progressed after initial therapy or have failed to respond to previous therapy. MF and SS are cancers in which lymphocytes become malignant (cancerous) and affect the skin. In MF, the disease is generally limited to the skin, and people develop flat or raised areas on their skin where the lymphocytes have accumulated. Sometimes even larger aggregations of lymphocytes occur in the skin or lymph nodes, resulting in tumors. In SS, the skin is often reddened or itchy, and some abnormal lymphocytes circulate in the blood. Atezolizumab is already used to treat adults with a cancer that affects the bladder and the urinary system, called urothelial carcinoma, and a cancer that affects the lungs, called non-small cell lung cancer. In standard practice, the disease will be treated with conventional chemotherapy that unfortunately has a limited lasting benefit. In this study, we want to see if a new treatment option can optimize and improve response and make benefit last as long as possible. This new treatment option is immunotherapy, using atezolizumab (Tecentriq). Immunotherapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal cells that may help cancer cell grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Atezolizumab blocks a protein called PD-L1 (programmed death-ligand 1) from binding to its receptor found on the surface of lymphocytes. It helps to restore the immune activity of the body against the cancer. Atezolizumab is already used to treat adults with a cancer that affects the bladder and the urinary system, and the lungs. | ||
Evidence for comparator |
This is a single arm study. Two arms were provided in various parts of this report due to EUDRACT reporting system limitation. | ||
Actual start date of recruitment |
22 Oct 2018
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
2 Years | ||
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 |
Switzerland: 2
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Country: Number of subjects enrolled |
Spain: 8
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Country: Number of subjects enrolled |
Austria: 2
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Greece: 1
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Country: Number of subjects enrolled |
Italy: 4
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Worldwide total number of subjects |
26
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EEA total number of subjects |
24
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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 |
16
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85 years and over |
0
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Recruitment
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Recruitment details |
Following the occurrence of three toxic deaths, an urgent safety measure was put in place and the study was prematurely closed for accrual. At the time of closure, a total of 26 patients had been registered by 7 institutions in 7 countries between 23/10/2018 and 16/09/2019. Nine of the 26 patients did not meet the eligibility criteria. | ||||||||||||||||
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Pre-assignment
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Screening details |
•Male or female patients with diagnosis of CTCL (MF or SS) tumor stage IIB to IVB •Inadequate response or secondary treatment failure to at least 1 prior systemic therapy for CTCL according to treatment guidelines •Age ≥ 18 years old •WHO performance status 0-1 •Adequate bone marrow and organ function prior to receiving the study treatment | ||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
26 | ||||||||||||||||
Number of subjects completed |
26 | ||||||||||||||||
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Period 1
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Period 1 title |
Overall period - Full patient population
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
Blinding implementation details |
NA
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Arms
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Arm title
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Atezolizumab | ||||||||||||||||
Arm description |
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. cycle. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Atezoluzimab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day.
Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria. Those patients for whom a clinical benefit is documentable at 1 year will be given the possibility to prolong the treatment for a maximum of two additional years unless a withdrawal criterion occurs earlier. In case of any additional adverse event grade 4 or higher is observed, the treatment will be permanently discontinued for all patients.
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Baseline characteristics reporting groups
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Reporting group title |
Atezolizumab
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Reporting group description |
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. cycle. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intention-to-treat Population
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Subject analysis set type |
Intention-to-treat | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All registered patients.
All 26 enrolled patients started atezolizumab in this study and were reviewed for eligibility by the project physician and approved by the study coordinator. Nine patients were considered to be ineligible.
Major deviations included;
-Retinoid treatment ongoing at start of study
-Prostate adenocarcinoma diagnosed in 2018
-Targetrin treatment stopped at start of study treatment instead of 4 weeks before
-Latent tuberculosis treated with rifampicin
Uncontrolled diabetes
-Uncontrolled diabetes with glycated hemoglobin above normal ranges
-Tuberculosis infection
-Tagretin and octagam (igg) washout not respected
-No data on glucose level at baseline but patient is diabetic
-Deep venous thrombosis and pulmonary embolism resolved 1 week prior to enrollment
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Subject analysis set title |
Per protocol Population
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Subject analysis set type |
Per protocol | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All registered patients who are eligible and have started atezolizumab treatment
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End points reporting groups
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Reporting group title |
Atezolizumab
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Reporting group description |
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. cycle. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria. | ||
Subject analysis set title |
Intention-to-treat Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All registered patients.
All 26 enrolled patients started atezolizumab in this study and were reviewed for eligibility by the project physician and approved by the study coordinator. Nine patients were considered to be ineligible.
Major deviations included;
-Retinoid treatment ongoing at start of study
-Prostate adenocarcinoma diagnosed in 2018
-Targetrin treatment stopped at start of study treatment instead of 4 weeks before
-Latent tuberculosis treated with rifampicin
Uncontrolled diabetes
-Uncontrolled diabetes with glycated hemoglobin above normal ranges
-Tuberculosis infection
-Tagretin and octagam (igg) washout not respected
-No data on glucose level at baseline but patient is diabetic
-Deep venous thrombosis and pulmonary embolism resolved 1 week prior to enrollment
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Subject analysis set title |
Per protocol Population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
All registered patients who are eligible and have started atezolizumab treatment
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End point title |
Overall response rate (ORR) | |||||||||||||||
End point description |
Overall response rate (ORR) is defined as the proportion of patients who achieved complete response (CR) or partial response (PR) as best result up to maximum of 1 year from patient registration.
The study was designed to reject the null hypothesis (H0: ORR=40%) with 90% power under the alternative hypothesis (H1: ORR=65%) using an exact binary test at 10% significance level 1-sided.
A total of 29 eligible patients were needed. The drug would be considered to warrant further investigation if 16 or more out of 29 eligible patients who start treatment were responders (CR or PR).
At the time of premature closure, there were only 17 eligible patients. Given the observed sample size , we assumed the same design; H0: ORR=40%, H1: ORR=65% and alpha=0.1. Based on this, with 78% power, at least 10 out of 17 eligible patients should be responders (CR or PR) for the drug to be considered worthwhile for further investigation (exact Type I error = 9.2% and power=78.7%).
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End point type |
Primary
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End point timeframe |
ORR is defined as the proportion of patients who achieved CR or PR as best result up to maximum of 1 year from patient registration.
This is a single arm assessment. This endpoint was analysed in the per-protocol.
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| Notes [1] - All registered patients who started atezolizumab. [2] - All eligible patients who started atezolizumab. |
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Statistical analysis title |
Best overall response rate (CR/PR) | |||||||||||||||
Statistical analysis description |
All patients achieving CR or PR are counted as success. All other cases will be considered as failures. ORR will be calculated by summing the number of participants assessed as having a CR or PR and dividing this by the total number of patients who are eligible and started treatment.
This is a single arm assessment. Two arms were provided due to EUDRACT reporting system limitation. This endpoint was analysed in the per-protocol population.
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Comparison groups |
Per protocol Population v Intention-to-treat Population
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Number of subjects included in analysis |
43
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | |||||||||||||||
Method |
exact binary test | |||||||||||||||
Parameter type |
Proportion-Exact binomial 1-sided 90% CI | |||||||||||||||
Point estimate |
17.6
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Confidence interval |
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level |
90% | |||||||||||||||
sides |
1-sided
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lower limit |
6.6 | |||||||||||||||
upper limit |
- | |||||||||||||||
| Notes [3] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation This analysis was performed in the per protocol population only |
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End point title |
Progression free survival (PFS) | ||||||||||||
End point description |
Progression-free survival (PFS) is defined as the time from treatment start to the first date of progressive disease or death from any cause. For patients who did not progress or die, this endpoint will be censored on the date of last disease assessment
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End point type |
Secondary
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End point timeframe |
Progression-free survival (PFS) is defined as the time from treatment start to the first date of progressive disease or death from any cause.
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| Notes [4] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation [5] - This analysis was only performed in the per protocol population |
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Statistical analysis title |
Secondary: PFS (per protocol population) | ||||||||||||
Statistical analysis description |
Progression free survival (PFS) will be analyzed as time to event endpoints. Median PFS will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method.
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Comparison groups |
Per protocol Population v Intention-to-treat Population
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Number of subjects included in analysis |
43
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Analysis specification |
Pre-specified
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Analysis type |
other [6] | ||||||||||||
Method |
Kaplan-Meier | ||||||||||||
Parameter type |
Median PFS estimate | ||||||||||||
Point estimate |
3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.4 | ||||||||||||
upper limit |
4.9 | ||||||||||||
| Notes [6] - This is a single arm assessment and PFS was performed only in the per protocol population. Two arms were provided due to EUDRACT reporting system limitation. |
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Statistical analysis title |
Other specified: PFS (ITT population) | ||||||||||||
Statistical analysis description |
This is a single arm assessment and this analysis was performed only in the intent-to-treat population. Two arms were provided due to EUDRACT reporting system limitation.
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Comparison groups |
Intention-to-treat Population v Per protocol Population
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Number of subjects included in analysis |
43
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | ||||||||||||
Method |
Kaplan-Meier | ||||||||||||
Parameter type |
Median PFS estimate | ||||||||||||
Point estimate |
3.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.4 | ||||||||||||
upper limit |
4 | ||||||||||||
| Notes [7] - Progression free survival (PFS) will be analyzed as time to event endpoints. Median PFS will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method. This is a single arm assessment. Two arms were provided due to EUDRACT reporting system limitation. |
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End point title |
Overall survival (OS) | ||||||||||||
End point description |
Overall survival (OS) is defined as the time from treatment start to the date of death from any cause.
Patients who are still alive will be censored at the last date documented to be alive.
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End point type |
Secondary
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End point timeframe |
Overall survival (OS) is defined as the time from treatment start to the date of death from any cause.
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| Notes [8] - This is a single arm test. Two arms are provided due to EUDRACT limitation. 999=estimate not reached [9] - This analysis was only performed in the per protocol population. 999=estimate not reached |
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Statistical analysis title |
Secondary: OS(per protocol population) | ||||||||||||
Statistical analysis description |
Median OS will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method.
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Comparison groups |
Intention-to-treat Population v Per protocol Population
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Number of subjects included in analysis |
43
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Analysis specification |
Pre-specified
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Analysis type |
other [10] | ||||||||||||
Method |
Kaplan-Meier | ||||||||||||
Parameter type |
Median OS estimate | ||||||||||||
Point estimate |
33.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
16.5 | ||||||||||||
upper limit |
999 | ||||||||||||
| Notes [10] - This is a single arm assessment and OS was performed only in the per protocol population. Two arms were provided due to EUDRACT reporting system limitation. Note 999= No estimate |
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Statistical analysis title |
Other specified: OS(ITT population) | ||||||||||||
Comparison groups |
Intention-to-treat Population v Per protocol Population
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Number of subjects included in analysis |
43
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Analysis specification |
Pre-specified
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Analysis type |
other [11] | ||||||||||||
Method |
Kaplan-Meier | ||||||||||||
Parameter type |
Median OS estimate | ||||||||||||
Point estimate |
999
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
999 | ||||||||||||
upper limit |
999 | ||||||||||||
| Notes [11] - Median OS was not reached. 999=estimate not reached |
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End point title |
Time to response | |||||||||||||||
End point description |
Time to response is defined as the time from treatment start until the time measurement criteria for CR/PR (whichever is first recorded) are first met. For patients who did not reach CR/PR, this endpoint will be censored on the date of last disease assessment during treatment. Going off protocol treatment without achieving CR/PR is considered a competing risk.
This is a single arm assessment, presented separately in the per-protocol and Intention-to-treat populations.
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End point type |
Secondary
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End point timeframe |
Time to response is defined as the time from treatment start until the time measurement criteria for CR/PR (whichever is first recorded) are first met.
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| Notes [12] - This is a single arm assessment. Results were presented in the intention-to-treat population [13] - This is a single arm assessment. Results were presented in the per-protocol population |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Response duration | ||||||||||||
End point description |
Response duration is defined as the interval from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that progressive disease is objectively documented. This endpoint is defined only in the subset of patients who achieve CR/PR. For patients who did not progress, this endpoint will be censored on the date of last disease assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Response duration is defined as the interval from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that progressive disease is objectively documented.
|
||||||||||||
|
|||||||||||||
| Notes [14] - This is a single arm assessment. This endpoint was analysed only in the per-protocol population [15] - Amongst the 4 patients who achieved CR/PR in the per- protocol population, two patients progressed |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to next systemic treatment | ||||||||||||
End point description |
Time to next systemic treatment is defined as the time from initiation of the current atezolizumab treatment until the time the next systemic treatment is recorded. For patients who did not have the record of next systemic treatment, this endpoint will be censored on the date of last adequate follow-up assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Time to next systemic treatment is defined as the time from initiation of the current atezolizumab treatment until the time the next systemic treatment is recorded.
|
||||||||||||
|
|||||||||||||
| Notes [16] - Note: This is a single are study . Here, the analysis is performed in the ITT-population [17] - Note: This is a single are study . Here, the analysis is performed in the per- protocol population |
|||||||||||||
Statistical analysis title |
Secondary: Time to next systemic treatment-per pro | ||||||||||||
Statistical analysis description |
Analysis will be performed in per-protocol population. Median Time to next systemic treatment will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method.
Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations
|
||||||||||||
Comparison groups |
Intention-to-treat Population v Per protocol Population
|
||||||||||||
Number of subjects included in analysis |
43
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [18] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Median time to next systemic treatment | ||||||||||||
Point estimate |
5.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
2.8 | ||||||||||||
upper limit |
33.4 | ||||||||||||
| Notes [18] - Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations |
|||||||||||||
Statistical analysis title |
Other specified: Time to next systemic treatment | ||||||||||||
Statistical analysis description |
Analysis will be performed in ITT population. Median Time to next systemic treatment will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method.
Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations
|
||||||||||||
Comparison groups |
Intention-to-treat Population v Per protocol Population
|
||||||||||||
Number of subjects included in analysis |
43
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [19] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Median time to next systemic treatment | ||||||||||||
Point estimate |
6.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
3.1 | ||||||||||||
upper limit |
14.8 | ||||||||||||
| Notes [19] - Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations. Analysis will be performed in ITT population. |
|||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Best overall response(1 year) | |||||||||||||||||||||||||||
End point description |
All patients included in the study will be assessed for global response every 12 weeks (4 cycles), even if there is a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), relapse, early death or not evaluable.
PD may be declared based on intermediate 6 weekly (every 2 cycles) blood and skin assessment.
To be assigned a status of CR or PR the response must be confirmed by an assessment performed 4-8 weeks after the criteria for response are first met.
|
|||||||||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||||||||
End point timeframe |
Best overall response achieved (according to EORTC-ISCL-USCLC criteria) within 1 year from registration.
This is a single arm assessment, presented separately in the per-protocol and Intention-to-treat populations.
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| Notes [20] - This is a single arm assessment. These results are based on the Intention-to-treat population. [21] - This is a single arm assessment. These results are based on the per-protocol population. |
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Best overall response(Follow-up) | |||||||||||||||||||||||||||
End point description |
All patients included in the study will be assessed for global response every 12 weeks (4 cycles), even if there is a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), relapse, early death or not evaluable.
PD may be declared based on intermediate 6 weekly (every 2 cycles) blood and skin assessment.
To be assigned a status of CR or PR the response must be confirmed by an assessment performed 4-8 weeks after the criteria for response are first met.
|
|||||||||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||||||||
End point timeframe |
Best overall response achieved (according to EORTC-ISCL-USCLC criteria) from registration throughout follow-up evaluations.
This is a single arm assessment, presented separately in the per-protocol and Intention-to-treat populations.
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| Notes [22] - This is a single arm assessment. Results were presented Intention-to-treat population [23] - This is a single arm assessment. Results were presented in the per-protocol population |
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
||||||||||||||||
End point title |
Overall response rate (ORR)-ITT Population | |||||||||||||||
End point description |
Standard disease assessment of tumour response status was performed every 2 cycles for skin and blood, and every 4 cycles for lymph nodes and visceral organs by local investigator according to EORTC/ISCL criteria allowing a global response call every 4 cycles. All patients achieving CR or PR are counted as success. All other cases will be considered as failures.
ORR will be calculated by summing the number of participants assessed as having a CR or PR and dividing this by the total number of patients who are eligible and started treatment.
This is a single arm assessment. This endpoint was analysed in the ITT-population.
|
|||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||
End point timeframe |
Overall response rate (ORR) is defined as the proportion of patients who achieved complete response (CR) or partial response (PR) as best result up to maximum of 1 year from patient registration.
|
|||||||||||||||
|
||||||||||||||||
| Notes [24] - This is a single arm study. Here, ORR was assessed in the ITT population [25] - This is a single arm study. Here, ORR was assessed in the per-protocol population |
||||||||||||||||
Statistical analysis title |
Other specified: ORR (ITT population) | |||||||||||||||
Statistical analysis description |
The study was designed to reject the null hypothesis (H0: ORR=40%) with 90% power under the alternative hypothesis (H1: ORR=65%) using an exact binary test at 10% significance level 1-sided.
A total of 29 eligible patients who start treatment were required, among whom 16 or more needed to responders (CR or PR) to declare the study a success.
Note: This is a single are study . The primary test will only be done in the per-protocol population.
|
|||||||||||||||
Comparison groups |
Intention-to-treat Population v Per protocol Population
|
|||||||||||||||
Number of subjects included in analysis |
43
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
other [26] | |||||||||||||||
Method |
Proportion-Exact binomial 1-sided 90% CI | |||||||||||||||
Parameter type |
Binomial proportion | |||||||||||||||
Point estimate |
15.4
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
90% | |||||||||||||||
sides |
1-sided
|
|||||||||||||||
lower limit |
6.8 | |||||||||||||||
upper limit |
- | |||||||||||||||
| Notes [26] - This is a single arm assessment. This endpoint was analysed here in the ITT population |
||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events, laboratory and physical abnormalities were collected till three months after the end of
treatment. Afterwards, only treatment related AE are collected. For SAEs: all SAEs till 30 days after end
of treatment; afterwards, only related SAEs
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (xx% AEs are reported as "other" and are not reported as not available from the list of SOC).
AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ARM A - Atezolizumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||||||
Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
01 Jul 2020 |
A scientific amendment (1652 protocol v7.0 20200701) took place on the 01/07/2020, due to a safety concern. The specific rationale for the amendment and its classification were:
1. The amendment followed an Urgent Safety Measures (USM) procedure. This Urgent Safety Measure procedure entailed the immediate closure of the trial recruitment on the 04/10/2019, following the occurrence of three sepsis-related deaths. Although the death event was deemed related to atezolizumab by the investigator only in one of these three cases, the sponsor in agreement with the study coordinators and the Chair of the EORTC CTCL Task Force decided to stop the recruitment. However, patients for whom a therapy effect was documentable were given the possibility to continue the treatment provided that they were properly informed about the USM by the investigator and they signed a PISIC addendum. An Urgent Safety Measures Letter has been sent to sites.
2. Treatment prolongation beyond 1 year for those patients who still benefit from atezolizumab at the treatment completion was extensively discussed with Study Coordinators and Roche. Given the strong ethical implications of stopping the treatment when clinical benefit is still documentable, especially in patients for whom not many therapeutic options are available, the company agreed on the extended drug supply.
3. Mandatory updates and changes concerning atezolizumab-related adverse events have been implemented in order to align with the newest IB (v 15) and addendum 2.
4. With the current sample size, this study is underpowered for the primary endpoint. Therefore a revised statistical analysis plan (SAP) provided details on the modification of the initial analysis plan of the EORTC protocol 1652 version 6 in light of the limited sample size. The revised SAP also includes some additional descriptive analysis of the efficacy and safety endpoints.
5. Addendum 2 v1.0 to PISIC v 3.0 for patient consent to stay on treatment beyond 1 year |
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| We did not meet the minimum number of responders needed to declare the trial as successful. A reason for this could be that the study was underpowered (78.7%) following premature closure. Only 17 eligible patients were enrolled instead of 29. | |||||||
