Pleura MesotheliomaPhase 2DiademNCT04115111
Diadem to Investigate the Activity and Safety of Durvalumab
A Phase 2 study testing Durvalumab in people with Pleura Mesothelioma, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
Trial summary
Malignant pleural mesothelioma (MPM) is a cancer with high mortality rate and few therapeutic options.essentially all patients usually progress and die subsequently to a first line therapyl. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pleura Mesothelioma
- What is being tested?
- Durvalumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 1 siteItaly
- Study dates
- 17 Oct 2018to 16 May 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histological diagnosis of advanced unresectable MPM;
- Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at least 5 unstained slides for central determination of PD-L1 expression;
- Aged ≥ 18 years;
- Performance status 0-1 (ECOG);
- Measurable disease as defined by Modified RECIST v1.1 for MPM;
- One previous chemotherapy line for MPM, based on pemetrexed plus platinum derivative combination;
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- Previous chemotherapy course concluded at least 4 weeks prior to recruitment;
- Signed informed consent;
- Negative pregnancy test. All patients in reproductive age or potential must agree to use effective contraception, as defined by the study protocol for the entire duration of treatment with study drug and for 3 months following its interruption;
- Patients who have received palliative radiation are eligible if <30% of bone marrow was irradiated and normal hematological function was completely regained;
- Adequate organ and marrow function as defined below: Haemoglobin ≥ 9.0 g/dL, Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3), Platelet count ≥ 100 x 109/L (>100,000 per mm3);
- Adequate liver function: Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (except for patients confirmed Gilbert's syndrome, who will be allowed only in consultation with their physician); AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN;
- Adequate renal function: Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
Who cannot join
- Radiotherapy with curative intent to thoracic wall (concomitant with or prior to chemotherapy);
- Severe concomitant illness;
- History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis;
- Any other anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent);
- History of primary immunodeficiency;
- HIV( Ab anti HIV+), active TB infection , HBV or HCV infection;
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- History of allogeneic organ transplant;
- History of hypersensitivity to durvalumab or any excipient;
- Any condition that, in the opinion of the investigator, would interfere with study treatment or patient safety;
- History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated, melanoma stage one, prostate adenocarcinoma, bladder cancer), unless in remission for 3 years or more and judged of negligible potential of relapse;
- Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment, uncontrolled arterial hypertension or arrhythmias;
- Brain / leptomeningeal involvement;
- Any previous treatment with a PD-1 or PD-L1 inhibitor, including Durvalumab;
- AEs from prior anticancer therapy that have not resolved to grade ≤ 1 except for alopecia
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase II Study to Investigate the Activity and Safety of Anti-PD-L1 Antibody (Durvalumab) In ADvancEd Pretreated Malignant Pleural Mesothelioma - DIADEM Study
Malignant pleural mesothelioma (MPM) is a cancer with high mortality rate and few therapeutic options.essentially all patients usually progress and die subsequently to a first line therapyl. There is strong evidence that the immune system is deeply involved in the biogenesis of MPM and that an imbalance in pro-inflammatory cytokines and exhausted adaptive T-cell mediated immune response are the main causes of neoangiogenesis, progression and metastatisation processes.Numerous Phase II-III clinical trials are underway evaluating Durvalumab either as monotherapy or combination with evidence of activity in a wide range of solid tumors. Durvalumab has received FDA approval as second line treatment in patients with locally advanced or metastatic urothelial carcinoma.
Given these prospects for PD-L1 Ab, a Phase II study is proposed in order to evaluate the activity and safety of Durvalumab in advanced pretreated MPM.
Read the detailed description
Malignant pleural mesothelioma (MPM) is a cancer with high mortality rate and few therapeutic options. Its incidence is growing fast worldwide and is associated with asbestos exposure, a well known cancerogenic factor driving the development of this cancer. Generally MPM is diagnosed at an advanced inoperable stage and most frequently the only therapeutic approach is palliative chemotherapy. Platinum-pemetrexed doublets prolong significantly median overall survival (OS) and median progression free survival (PFS) with respect to platinum alone and are considered the only therapeutic option in a first line setting. Unfortunately, essentially all patients usually progress and die subsequently to a first line therapyl. There is strong evidence that the immune system is deeply involved in the biogenesis of MPM and that an imbalance in pro-inflammatory cytokines and exhausted adaptive T-cell mediated immune response are the main causes of neoangiogenesis, progression and metastatisation processes. Newer immunotherapeutic agents act on regulatory molecules expressed on immune cells in order to increase T cell activity and immune response against tumor. The anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) demonstrated activity and a long-term disease control (DC) rate in advanced pretreated MPM in phase II study even if these results are not confirmed in more recently Phase IIb randomized trial versus placebo (DETERMINE study). Antibodies against Programmed Death 1 receptor (PD-1) and its ligand (PD-L1) are highly promising new agents regulating immune check-point processes. In particular the interaction of these agents takes place peripherally more than in the lymphoid tissue and may explain the higher response rate and lower adverse immune effects in comparison to antiCTLA4 agents. AntiPD-L1 antibodies are widely studied in many Phase I-II trials in different advanced pretreated solid tumors independent of tumor PD-L1 expression, with promising results and long-term survival. Ongoing melanoma and lung cancer phase III trials would probably better define the role of this class of drugs in clinical practice. Durvalumab is a human IgG1 antibody which binds specifically to PD-L1, preventing binding to PD-1 and CD80. Numerous Phase II-III clinical trials are underway evaluating Durvalumab either as monotherapy or combination with evidence of activity in a wide range of solid tumors. Durvalumab has received FDA approval as second line treatment in patients with locally advanced or metastatic urothelial carcinoma.
Given these prospects for PD-L1 Ab, a Phase II study is proposed in order to evaluate the activity and safety of Durvalumab in advanced pretreated MPM.
- Conditions
- Pleura Mesothelioma
- Being tested
- Durvalumab
- Keywords
- malignant pleural mesothelioma
- Medical subject headings
- Mesothelioma, Malignant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DurvalumabDrug
Durvalumab in monotherapy as second line treatment
| Study group | Role | What they receive |
|---|---|---|
| Durvalumab arm | Experimental | Patients will receive Durvalumab at the dose and regimens described above every 4 weeks until evidence of disease progression or occurrence of unacceptable toxicity.
Patients who show evidence of disease progression but appear to tolerate Durvalumab well, for whom no other treatment options exist and who, at the judgement of the investigator, may still enjoy clinical benefit, will be classified as failures and offered the possibility to continue treatment with extended follow up. Receives: Drug: Durvalumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of survived patients at 16 weeks
Proportion of patients alive and free from progression or death at 16 weeks (PFS 16 w) calculated from the start of treatment (Durvalumab).
Measured: 16 weeks
Secondary outcomes (6)
Progression free survival
defined as the time from treatment start to progression of disease or death from any cause; in absence of an event, patients will be censored at the time of the latest date of assessment. If the patient has no evaluable visits or does not have baseline data they will be censored at 1 day.
Measured: 16 weeks
overall survival
defined as the time from treatment start to death from any cause; in absence of an event, patients will be censored at the time of the latest date of assessment. If the patient has no evaluable visits or does not have baseline data they will be censored at 1 day.
Measured: 16 weeks
Objective response rate
defined as the proportion of patients with complete response (CR) or partial response (PR) according to CT assessment using the RECIST v1.1 criteria modified for MPM (Modified RECIST). Independent central review will be used to confirm investigator ORR.
Measured: 16 weeks
Tumour growth index
defined as the ratio between PFS and the time from treatment start to progression of disease in first-line treatment
Measured: 16 weeks
Evidence of Number of Adverse Events
Evaluated based on frequency, type and severity of reported AEs, immune related irAE, clinical laboratory assessments, vital signs and physical examination. Adverse events will be encoded and graded using NCI-CTCAE version 4.03.
Measured: 16 weeks
Exploratory endpoint
PD-L1 IHC expression in tumor samples and tumor infiltrating lymphocytes (TIL), measured with the validated ABCAM 28-8 assay IHC assay optimized for use on the automated BenchMark UTRA platform (Ventana Medical Systems, Tucson, AZ, USA).
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2019
- Study start17 Oct 2018
- Primary completion16 May 2019
- Study completion16 May 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pleura MesotheliomaStudies of the same condition, open and under way.
- More trials run by Mario Negri Institute for Pharmacological ResearchThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Diego Cortinovis, MD, Principal investigator, ASST-Monza San Gerardo Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04115111
- Sponsor's protocol ID
- IRFMN-MPM-7109
- Acronym
- Diadem
- Status last verified
- Mar 2023
- First submitted
- 2 Oct 2019
- Last updated
- 15 Mar 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Canova S, Ceresoli GL, Grosso F, Zucali PA, Gelsomino F, Pasello G, Mencoboni M, Rulli E, Galli F, De Simone I, Carlucci L, De Angelis A, Belletti M, Bonomi M, D'Aveni A, Perrino M, Bono F, Cortinovis DL; DIADEM groupD. Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma. ESMO Open. 2022 Dec;7(6):100644. doi: 10.1016/j.esmoop.2022.100644. Epub 2022 Dec 1.
PubMed 36463732
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study to Investigate the Activity and Safety of Anti-PD-L1 Antibody (Durvalumab) In ADvancEd Pretreated Malignant Pleural Mesothelioma - DIADEM Study
- ClinicalTrials.gov ID
- NCT04115111
- Acronym / sponsor ID
- Diadem / IRFMN-MPM-7109
- Conditions
- Pleura Mesothelioma
- Keywords
- malignant pleural mesothelioma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 57 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Study start
- 17 Oct 2018 (actual)
- Primary completion
- 16 May 2019 (actual)
- Study completion
- 16 May 2019 (actual)
- First posted
- 3 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Malignant pleural mesothelioma (MPM) is a cancer with high mortality rate and few therapeutic options.essentially all patients usually progress and die subsequently to a first line therapyl. There is strong evidence that the immune system is deeply involved in the biogenesis of MPM and that an imbalance in pro-inflammatory cytokines and exhausted adaptive T-cell mediated immune response are the main causes of neoangiogenesis, progression and metastatisation processes.Numerous Phase II-III clinical trials are underway evaluating Durvalumab either as monotherapy or combination with evidence of activity in a wide range of solid tumors. Durvalumab has received FDA approval as second line treatment in patients with locally advanced or metastatic urothelial carcinoma.
Given these prospects for PD-L1 Ab, a Phase II study is proposed in order to evaluate the activity and safety of Durvalumab in advanced pretreated MPM.
Detailed description
Malignant pleural mesothelioma (MPM) is a cancer with high mortality rate and few therapeutic options. Its incidence is growing fast worldwide and is associated with asbestos exposure, a well known cancerogenic factor driving the development of this cancer. Generally MPM is diagnosed at an advanced inoperable stage and most frequently the only therapeutic approach is palliative chemotherapy. Platinum-pemetrexed doublets prolong significantly median overall survival (OS) and median progression free survival (PFS) with respect to platinum alone and are considered the only therapeutic option in a first line setting. Unfortunately, essentially all patients usually progress and die subsequently to a first line therapyl. There is strong evidence that the immune system is deeply involved in the biogenesis of MPM and that an imbalance in pro-inflammatory cytokines and exhausted adaptive T-cell mediated immune response are the main causes of neoangiogenesis, progression and metastatisation processes. Newer immunotherapeutic agents act on regulatory molecules expressed on immune cells in order to increase T cell activity and immune response against tumor. The anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) demonstrated activity and a long-term disease control (DC) rate in advanced pretreated MPM in phase II study even if these results are not confirmed in more recently Phase IIb randomized trial versus placebo (DETERMINE study). Antibodies against Programmed Death 1 receptor (PD-1) and its ligand (PD-L1) are highly promising new agents regulating immune check-point processes. In particular the interaction of these agents takes place peripherally more than in the lymphoid tissue and may explain the higher response rate and lower adverse immune effects in comparison to antiCTLA4 agents. AntiPD-L1 antibodies are widely studied in many Phase I-II trials in different advanced pretreated solid tumors independent of tumor PD-L1 expression, with promising results and long-term survival. Ongoing melanoma and lung cancer phase III trials would probably better define the role of this class of drugs in clinical practice. Durvalumab is a human IgG1 antibody which binds specifically to PD-L1, preventing binding to PD-1 and CD80. Numerous Phase II-III clinical trials are underway evaluating Durvalumab either as monotherapy or combination with evidence of activity in a wide range of solid tumors. Durvalumab has received FDA approval as second line treatment in patients with locally advanced or metastatic urothelial carcinoma.
Given these prospects for PD-L1 Ab, a Phase II study is proposed in order to evaluate the activity and safety of Durvalumab in advanced pretreated MPM.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Durvalumab arm | Experimental | Drug: DurvalumabPatients will receive Durvalumab at the dose and regimens described above every 4 weeks until evidence of disease progression or occurrence of unacceptable toxicity. Patients who show evidence of disease progression but appear to tolerate Durvalumab well, for whom no other treatment options exist and who, at the judgement of the investigator, may still enjoy clinical benefit, will be classified as failures and offered the possibility to continue treatment with extended follow up. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Histological diagnosis of advanced unresectable MPM;
- Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at least 5 unstained slides for central determination of PD-L1 expression;
- Aged ≥ 18 years;
- Performance status 0-1 (ECOG);
- Measurable disease as defined by Modified RECIST v1.1 for MPM;
Key exclusion criteria (14 listed)
- Radiotherapy with curative intent to thoracic wall (concomitant with or prior to chemotherapy);
- Severe concomitant illness;
- History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis;
- Any other anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent);
- History of primary immunodeficiency;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DurvalumabDurvalumab in monotherapy as second line treatment | Drug | Durvalumab arm |
Primary outcome
Proportion of survived patients at 16 weeks
Time frame: 16 weeks
Proportion of patients alive and free from progression or death at 16 weeks (PFS 16 w) calculated from the start of treatment (Durvalumab).
6 secondary outcomes
Progression free survival
Time frame: 16 weeks
overall survival
Time frame: 16 weeks
Objective response rate
Time frame: 16 weeks
Tumour growth index
Time frame: 16 weeks
Evidence of Number of Adverse Events
Time frame: 16 weeks
Exploratory endpoint
Time frame: 16 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2023.
- Results publication: PubMed 36463732Canova S, Ceresoli GL, Grosso F, Zucali PA, Gelsomino F, Pasello G, Mencoboni M, Rulli E, Galli F, De Simone I, Carlucci L, De Angelis A, Belletti M, Bonomi M, D'Aveni A, Perrino M, Bono F, Cortinovis DL; DIADEM groupD. Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma. ESMO Open. 2022 Dec;7(6):100644. doi: 10.1016/j.esmoop.2022.100644. Epub 2022 Dec 1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diego Cortinovis, MD principal investigator
ASST-Monza San Gerardo Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Durvalumab in people with Pleura Mesothelioma, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of survived patients at 16 weeks (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04115111, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2023.